AMR Final Exam (Cumulative)
3 classes of 23S rRNA mutations of 50S (MLSB) post-translational modification (decreases binding affinity by changing/hindering binding site)? *all bind to 50S subunit of bacterial ribosome.
macrolide, lincosamide, & streptogramin B
antibiotics can ____ resistance genes between bacteria.
mobilize
allow transport of relatively small molecules (e.g., B-lactams, chloramphenicols, quinolones, & tetracyclines) across the outer membrane; like efflux pump, these are predominantly found in gram (-) bacteria.
porins
B-lactam antibiotics are more effective in gram-_____ bacteria, due to different membrane structures.
positive
Enterococcus faecium is gram-_____.
positive
S. aureus is a gram-_____.
positive
Tet(O) binds to the tetracycline-blocked ribosome leading to conformation changes that release _____; then, Tet(O) leaves its binding site, while the ribosome remains in a conformation that doesn't favor _____-binding.
tetracycline
how can we decrease transmission of MRSA?
- wash w/ soap & water. - use alcohol-based sanitizers. - keep cuts/scrapes clean & covered. - avoid contact w/ other people's wounds. - avoid sharing personal hygiene accessories (towels, razors, etc.).
more than ____ people get infected w/ STDs each day worldwide; estimated that 1 in 4 sexually active teens in the U.S. have an STD.
1 million
about ____ of bacteria in 1 acre of soil; this is the weight of a smart car.
1 ton
_____ of soil has about 100 million to 1 billion bacterial cells.
1 tsp
humans have at least as many bacteria inhabiting their bodies as number of their own cells (_____ trillion).
30-39
estimated that any single antibiotics is only useful for about ___ years, meaning that antibiotics discovered during "Golden Age" are at the end of their effectiveness.
50
Clinical Laboratory Standard Institute (CLSI) is an international organization that serves members from over _____ countries.
60
as of 2018, 68 of all enrolled countries are reporting to GLASS; this is a _____ increase compared to 2017; great progress.
64%
____ of all nosocomial bacterial infections are thought to be associated w/ biofilms.
65%
members of WHO are divided into regions (6 total) that include Africa, Americas, Pan-America, Eastern Mediterranean European, Southeast Asia, & Western Pacific: _____ of all members returned info on AMR surveillance, while only _____ returned data sets on antibiotic use.
66%; 59%
_____ also belongs to class 2, type II topoisomerases; paralog of DNA gyrase; facilitates DNA strand passing; relaxes positively supercoiled DNA; can also separate interlinked chromosomes; heterotetrametric (made of 2 subunits: ParC & ParE).
DNA topoisomerase IV
isolate the very genes that make the specific antigens the body needs to trigger the immune response to certain pathogens. doesn't contain other ingredients from rest of pathogen that would put patient at risk for developing disease.
DNA vaccines
when injected, genes instruct cells of body to make antigens to create stronger immune response & prepare body for future threats.
DNA vaccines
when antispetic technique wasn't used to control spread of ifnection.
Dark Ages
types of antibiotic target modification that involve the ribosomal alteration conferring antibiotic resistance.
- 23S rRNA Mutations of 50S (MLSB) - 16S rRNA mutations of 30S (aminoglycoside & tetracyclines)
classes of antibiotics that inhibit bacterial cell wall synthesis?
- B-lactams - Glycopeptides
we can become exposed to ABR thru water thru what?
- urban water - drinking water - recreational areas (can be contaminated thru runoff) - fresh produce
penicillin isolated & purified; chemical structure identified, & its crystal structure was determined/modified, so that it was useful as an oral antibiotic.
Florey
fluoroquinolones known to bind to ____ subunits.
GyrA
class 1 integrons are known to facilitate _____.
HGT
between ¼-1/3 of world's population is carrying dormant _____; show no symptoms of infection. however, others can be more susceptible such as young & old.
M. tuberculosis
statistical method used to estimate number of bacteria in liquid sample based on number of dilutions required to detect no growth.
MPN (most probable number)
promotes good lab practices & supports labs in national surveillance system.
National Reference Lab
over past 8 decades, _____ has been rapidly developing resistant to all antibiotics used against infection.
Neisseria gonorrheae
severe burns & cystic fibrosis patients are especially predisposed to _____ infections.
P. aeruginosa
malaria parasite, known as _____, develops resistance to anti-malaria drugs, posing serious threat, taking ½ million lives annually globally.
P. falciparum
Henrici named them ____, or what we now know as biofilms.
benthos
can happen thru genetic mutations or thru acquisition of genetic material from other resistant organisms; poses highest risk to people.
acquired ABR
declining due to permanent hearing loss & kidney toxicity (even for topical applications, neomycin); use has been reduced to topical, but hearing loss is still possible if neomycin ointment gets into body through open wounds.
aminoglycosides
in 16S rRNA mutations of 30S, _____ inhibit tRNA translocation from A to P site & cause misreading of mRNA.
aminoglycosides
type of antibiotics that cause kidney damage?
aminoglycosides
class of antibiotics that inhibits bacterial RNA synthesis?
ansamycins
current guidelines on prophylactic use of antibiotics for prevention of IE in U.S. & Europe: the rest of Europe & the U.S. continue recommending _____ for patients, who are at high risk of developing IE.
antibiotic prophylaxis
efflux pumps pump molecules out of cells; they can be _____ or _____ (can lead to MDR); provide _____ against antibiotic-producing bacteria; all require energy to move molecules across (_____).
antibiotic specific or broad; intrinsic; active transport
type of MOA that involves target modification; mutational alteration/enzymatic modification of antibiotic target.
antibiotic target modification
screening platform known as scope of search: one source that's naturally present as a defense mechanism are _____, which are synthesized by _____. e.g., blood from lizards & reptiles; venom.
antimicrobial peptides; ribosomes
block viral replications.
antiviral agents
potentially fatal disease characterized by drastic low level of blood cells; prevalence is 1:500k people.
aplastic anemia
person who carries an infective organism, but who does not manifest any signs of infection; therefore, unwillingly spreading the infection to other unaffected individuals.
asymptomatic carrier
for prevention & control: avoid _____ & hospitals.
injuries
MSSA is _____ S. aureus.
methicillin-sensitive
medium selection pressure manifested by use of manmade antibiotics; includes agri- & aquaculture.
non-clinical ecosystem
each one of the 5 classes of efflux pumps requires _____.
energy
example of a prodrug is _____ (first sulfa drug that gets activated by gut bacteria) & _____ (activated once inside of M. tuberculosis).
prontosil, isoniazid
serious side effects of chloramphenicol?
enhances cross reactivity of chloramphenicol against human mitochondrial ribosomes.
antibiotic stewardship
ensure all orders have dose, duration, & indications; get cultures before starting antibiotics; take "antibiotic timeout," reassessing antibiotic 48-72 hours.
C-55-isoprenyl pyrophosphate flippase is responsible for _____ molecules across the membrane.
flipping
molecule composed of combination of amino acids.
glycoprotein
____, meaning presence of antibiotics, can accelerate bacteria to acquire resistance & cause life-threatening infections.
high selective pressure
F positive donor cells are able to integrate their plasmid into their genomic DNA; such cells are referred to as ____.
high-frequency of recombination (Hfr)
Lipinski's "Rule of 5" Guidelines important for this type of screening platform called _____.
high-throughput screening (HTS)
_____ can enhance the discovery of species-specific compounds.
high-throughput screening (HTS)
other sources of natural or acquired ABR are?
wild animals & soil
untreated gonorrhea can cause serious health issues... women? men?
women: can increase their risk for a life-threatening ectopic pregnancy. women & men: can cause conditions that can lead to infertility & increase a person's risk of getting or giving HIV.
objectives of Global Antimicrobial Resistance Surveillance System (GLASS)?
- foster national surveillance systems & harmonized global standards. - estimate extent & burden of AMR globally by selected indicators. - analyze & report global data on AMR on a regular basis. - detect emerging resistance & its international spread. - inform implementation of targeted prevention & control programs. - assess the impact of interventions.
what do the ESKAPE pathogens all have in common?
- found in both developed & developing countries. - pathogenic. - transmissible. - highly resistant.
we can become exposed to ABR thru soil thru what?
- fresh produce - recreational areas - drinking water
____ of microbial genomes isolated from ocean water harbors bacteria from non-marine origin.
25%
out of 40M people annually who are prescribed antibiotics for respiratory issues, _____ get antibiotics unnecessarily while only _____ actually need them.
27M; 13M
bacterial cell has genome size of ____ Mbp w/ very little "junk" DNA.
3-9
types of bacterial diagnostics?
- growth conditions (different media types (i.e., basic, enriched, selective, differential, anaerobic) - morphological identification (microscopy & staining (motility, gram-stain, etc.)) - biochemical testing (coagulase, oxidase, urease, etc.) - antigen detection (ELISA, IF, agglutination, EIA, etc.) - serological diagnosis - molecular diagnostics ((FISH, PCR, RT-PCR, etc.) - rapid 7 most accurate results)
antimicrobials are used in agriculture for what 2 reasons?
- growth promotion - low-cost hygiene measures
common biofilm-harboring devices include?
- heart-associated implants (ventricular-associated devices, shunts, pacemakers, defibrillators, & valves) - mechanical ventilators & endotracheal intubation - catheters - breast implants - joint prosthetics
possible approaches to the fact that we're running out of targets to kill pathogenic bacteria?
- hemoperfusion devices - quorum sensing inhibitors - lytic bacteriophage - polyclonal/monoclonal antibodies; immune adjuvants - liposome-based cytotoxin inhibitors - nonimmune toleralizing approaches
why is it difficult to eliminate antibiotic use from farm animals?
- loss of profit to farm animal companies - uncontrolled access (no prescription needed for penicillin & streptomycin online)
resistance encoded in segments of DNA called antibiotic resistance genes (ARG's), which enable bacteria to fight antibiotics by various mechanisms including...
- modifying cellular target. - degrading/modifying antibiotic. - preventing uptake. - efflux - pumping of antibiotic out of cell.
in ATP-binding cassette F (ABC-F) ribosomal protection: _____ bind to ribosome & displace PTC & NPET-bound antibiotics. this family of _____ are only found in gram (+) bacteria (Streptomyces, Staphylococci, Streptococci, & Enterococci).
ATP-binding cassette F (ABC-F) family proteins
in bacteria, start codon ____corresponds to formylmethionine, rather than methionine. fMET is removed post-translationally; its presence in humans indicates presence of foreign bodies.
AUG
serious ABR threats in U.S.?
- multi-drug resistant Acinetobacter - drug-resistant Campylobacter - fluconazole-resistant Candida - extended spectrum B-lactamase-producing Enterobacteriaceae - vancomycin-resistant Enterococcus (VRE) - multi-drug resistant Pseudomonas aeruginosa - drug-resistant non-typhoidal Salmonella - drug-resistant Salmonella Serotype Typhi - drug-resistant Shigella - MRSA drug-resistant Streptococcus pneumoniae - drug-resistant tuberculosis
what are the most likely explanations of people who develop VRE?
- patients usually have underlying conditions such as chronic skin ulcers or diabetes - predisposes them to secondary infections. - had a previous treatment w/ vancomycin, which selected for vancomycin-resistant infection.
4 classes of b-lactam antibiotics that mimic D-Ala-D-Ala dipeptide?
- penicillins - cephalosporins - monobactams - carbapenems
specific targets in bacteria that won't interfere w/ humans?
- peptidoglycan of bacterial cell walls - 60S/40S ribosome of bacteria - RNA polymerase - isoleucyl-tRNA synthetase - folate synthesis (developed sulfa drugs)
what are some advanced treatment technologies for wastewater? *however, these technologies may be contributing to existence of ARB by increasing bacterial mutation rate.
- photocatalysis - membrane filtration - activated carbon absorption - advanced oxidation processes (AOP's)
4 core actions to help fight deadly infections?
- prevent infection & spread of resistance. - track resistant bacteria. - improve use of today's antibiotics. - promote development of new antibiotics & develop new diagnostic tests for resistant bacteria.
advantages of host-directed antimicrobial therapeutics over antibiotics?
- prevent/enhance bacterial uptake. - enhance human cells to kill bacteria. - target host resources essential for intracellular survival & replication of pathogen. - circumvent antibiotic resistance.
4 core actions to battle ABR recommended by CDC?
- preventing infections & spread of resistance. - avoiding infections in 1st place reduces amount of antibiotic use. - proper education & common sense can prevent disaster. - implement control measures, which mostly rely on proper education & its common-sense application.
as part of the evidence-based approach to care, this AHA clinical recommendation should be integrated w/ practitioner's professional judgement in consultation w/ the patient's physician, & the patient's needs & preferences; these considerations include?
- previous artificial joint infections & complications - patients undergoing treatment of oral infections - increases susceptibility for systemic infections - immunodeficiencies & immunosuppressive medication - diabetes - autoimmune diseases (rheumatoid arthritis or lupus) - extensive & invasive procedures
methods used for analyzing antimicrobial resistant genes (ARG's)?
- quantitative PCR - metagenomics - functional metagenomics
3 possible scenarios for the diagnostic strategies that fuel AMR?
- semiprimal diagnosis - traditional diagnosis - rapid diangosis
antimicrobial peptides in venom may be found in what types of animals?
- snakes - spiders - scorpions - bees - cone snails
antibiotic genes become dangerous when...
- they up in a human pathogen. - are selected for.
STDs pose serious healthcare concern for several reasons. what are they?
- they're intracellular pathogens (unlike other bacteria we've talked about) - high selection for resistance - easily transmissible - high prevalence
characteristics of gram-positive bacteria?
- thick peptidoglycan layer (multilayered). - teichoic acids are present in many. - no periplasmic space. - no outer membrane. - virtually no LPS content. - flagellar structure: 2 rings in basal body. - produce primarily exotoxins. - mesosome more prominent. - more susceptible to antibiotics.
2 functions of antibiotics?
- to kill (bactericidal) - to inhibit (bacteriostatic)
clinical resistance is described by multiple factors such as...
- type of bacteria - infection site - antibiotic pharmacokinetics - immune response affecting clinical outcomes of antibiotic treatment
_____ of Anazarbos, a Greek surgeon who wrote book on natural remedies; ancient book holds forgotten remedies; book remained a standard reference for 1.5 centuries; describes over 5k unique therapeutic use of 536 plant taxa & 924 herbal drugs; recently published study analyzed all chapters to categorize all info to provide basis for future research on herbal drugs.
Pedanius Dioscorides
narrow-spectrum penicillins?
Penicillin G, Penicillin V, & methicillin.
initial _____ case officially isolated in 1997 in Japan, but previous reports suggest intermediate vancomycin resistance appeared in late 1980's.
VISA
while VRSA infections are very rare, _____ infections are more common.
VISA
2-component regulatory systems (TCRS) are also involved in sensing & inactivation of many antibiotics. e.g., ____ & ____ are responsible for detection of vancomycin or other glycopeptides, where VanS is a ____ that detects presence of extracellular glycopeptide & sends signal to VanR that activates ____ of vanHAX, HAX genes.
VanS; VanR; sensory kinase; transcription
bacteria alter membrane charge thru _____ (addition of amino acid, alanine) of anionic teichoic acids at gram (+) bacteria cell wall results in a net positive charge; cell wall itself has negative charge because of phospholipids & therefore, attracts cationic molecules.
alanylation
active agent not destroyed by boiling for few min., but boiling for 1 hour in _____ soln. markedly reduces antibacterial power.
alkaline
one study collected 412 samples of bacteria from soil to test for ABR, & _____ isolates were multi-drug resistant.
all
types of adverse drug event related to antibiotics?
allergic reactions, C. difficile, cross-drug interactions & side effects
active ingredient of garlic; active against number of bacterial infections in in vitro studies; human studies failed to generate results; may be due to way the body metabolizes _____.
allicin
gastrointestinal side effects caused by which antibiotics?
almost all
alanylation: ______ of each alanine add a net positive charge to bacterial membrane, which electrostatically repel cationic compounds, including cationic antimicrobial peptides.
amine groups
_____ substitutions in DNA gyrase & topoisomerase IV result in a decrease of quinolone binding affinity.
amino acid
B-lactamase classification is based on _____ in their active site, & B-lactamases are divided into molecular classes, where a, c, & d class enzymes utilize serine for B-lactam hydrolysis.
amino acid sequence
presence of _____ on both ampicillin & amoxicillin allows them to penetrate outer membrane of gram-negative bacteria.
amino group
bacteria, like eukaryotic cells, require 20 _____, one for each of the 20 AA's; there are enough structural differences between bacterial & eukaryotic tRNA synthetases, that allows specificity for mupirocin to target bacterial but not eukaryotic tRNA synthetase.
aminoacyl tRNA synthetases
bacteria alter membrane charge thru _____ (glycosylation, addition of sugar moiety) of lipid A; represents mechanism by which bacteria add aminosugar moiety to lipid A; such modification results in the overall membrane charge increase resulting in an electrostatic repulsion of cationic antimicrobial peptides (i.e., polymyxins); mainly observed in LPS of gram (-) bacteria.
aminoarabinosylation
in charge alteration (type of antibiotic target modification), bacteria change the net charge of the membrane from negative to positive & do so by 3 different types: they are? result of any of these 3 modifications is overall increase in a positive charge leading to electrostatic repulsion of positively charged lipopeptide molecules.
aminoarabinosylation, lysinylation, & alanylation
antibiotics that target translation at the 30S ribosomal subunit; broad-spectrum, bactericidal antibiotics commonly prescribed for children, primarily for infections caused by gram (-) pathogens; include gentamicin, amikacin, tobramycin, neomycin, and streptomycin.
aminoglycosides
causes hearing loss?
aminoglycosides
class of antibiotics that target protein synthesis of 30S subunit; sometimes called oligosaccharide antibiotics. includes streptomycin, neomycin, kanamycin, & gentamicin; structure has amino sugars linked by glycosidic bonds; given in combo w/ b-lactams (bactericidal).
aminoglycosides
type of antibiotic target modification called ribosomal alteration conferring antibiotic resistance in 16S rRNA mutations of 30S involves _____ & _____ binding to 30S subunit of bacterial ribosome.
aminoglycosides & tetracyclines
in AmpG-AmpR-AmpC pathways in cytoplasm, ____ activates transcription of ampC or B-lactamase. ____ has other functions (i.e., in P. aeruginosa, it also induces proteases, quorum sensing, & other virulence factors).
ampR
use of antimicrobials in _____ has been linked to drug-resistant infections in humans & animals. in fact, inappropriate use of antimicrobials in _____ is the leading cause of rising AMR.
animals
inhibit bacterial RNA synthesis; lipophilic macrocyclic antibiotics that easily diffuse through membranes; comprised of 2 aromatic rings (containing a quinone), connected by a long chain (or 'ansa' - hence the name given to this class of antibiotics), which confers a rigid character to the whole molecule.
ansamycins
larger class of antibiotics characterized by an aromatic ring bridged by aliphatic chain; includes rifampin & metronidazole.
ansamycins
target parasites such as malaria.
anti-parasitic drugs
_____ most likely contribute to balance between resistant & sensitive bacteria.
anti-resistant mechanisms
natural _____ included naturally occurring B-lactams, which were precursors to the antibiotics we have today.
antibiosis
it's been demonstrated that _____ products revert bacteria from resistant to a sensitive variant.
antibiotic degradation
type of MOA that targets antibiotic availability; transport of antibiotics outside of cell.
antibiotic efflux
upon presence of selective pressure, a cell can completely lose its ability to make porins leading to a complete inhibition of _____.
antibiotic entry
type of MOA that directly targets antibiotic; enzymatic inactivation of antibiotic to confer drug resistance
antibiotic inactivation
where did antibiotic resistance come from?
antibiotic producers (same bugs that make the antibiotics)
however, some bacteria (e.g., Lactobacilli) that don't produce vancomycin but still use lactate in their pentapeptide of the lipid II molecule. Why?
antibiotic resistance must have come before antibiotics.
in biofilms, it's thought that it's the unfavorable conditions (e.g., low oxygen level, low pH, or low hydration level) that contributes the most to ____. not as much the slow penetration or physical barrier, but it's also the altered ____.
antibiotic resistance; microenvironment
once bacteria identified, need to determine _____ to ensure right treatment is applied; there are 3 methods.
antibiotic sensitivity
either hinder antibiotic binding site & prevent their binding or induce protein conformational changes that lead to antibiotic release.
antibiotic target protection
type of MOA that involves target modification; protection of antibiotic action target from antibiotic binding.
antibiotic target protection
many of the antibiotic-producing bacteria are non-pathogenic; however, major problem is the ability of _____ to jump between/within species.
antibiotic-resistant genes
ABR-infections cost more per person compared to _____.
antibiotic-sensitive infections
_____ & _____ are made by bacteria/other microorganisms, plants, & animals.
antibiotics & antimicrobial compounds
functions in natural environment; In soil, concentration of antibiotics is so low, that it's not considered toxic; if so, then they must be involved in other important functions that are yet to be discovered.
antibiotics as signals
pollutant compounds such as _____, _____, _____, & _____ all can promote HGT in wastewater among various bacterial species.
antibiotics, biocides, pharmaceuticals, & heavy metals
wastewater contains _____, _____, & _____, which can all form a selection pressure for ABR.
antibiotics, disinfectants, & metals
biofilms are resistant to ____ & other ____.
antibiotics; antiseptics
for prevention & control: never share/use leftover _____; prevent infections by regularly washing _____; avoiding close contact w/ _____people; practicing safer _____; & keeping _____ up to date.
antibiotics; hands; sick; sex; vaccinations
inhibit fungal growth or kill fungus.
antifungal agents
difficult to isolate these _____; may serve as alternatives to antibiotics.
antimicrobial peptides
ability of a microorganism (e.g., bacteria, viruses, & some parasites) to stop an antimicrobial (such as antibiotics, antivirals, & antimalarials) from working against it. As a result, standard treatments become ineffective, infections persist & may spread to others."
antimicrobial resistance
agricultural runoff & use of antibiotics in aquaculture contributes to non-marine origin of ocean AMR.
aqua-/agriculture
a bacterial biofilm is a surface-attached community; always occur in ____ environments.
aquatic
antimicrobial identification & antibiotic susceptibility tests are rapidly being _____ to increase efficacy, sensitivity, & turnaround time. however, many of these systems remain too expensive for general application, & use is restricted to areas w/ right resources such as electricity, proper housing, & adequate training, etc.
automated
_____ allows screening thousands of conditions.
automated microscopy
low concentration of _____ can kill P. aeruginosa in matter of minutes; can help prevent spread of bacteria in healthcare setting or other public areas.
copper
antimicrobial that combines a sulfa-drug (DHPS inhibitor) w/ trimethoprim (DHFR inhibitor); combination allows for lesser chance of developing resistance, because target 2 distinct enzymes in same pathway; creates synergistic effect.
cotrimoxazol
when foreign microbes invade us, immune system triggers responses to remove them. signs are _____, _____, _____, & _____: trap, deter, & rid body of threatening things like bacteria.
coughing, sneezing, inflammation, & fever
_____ leads to human exposure potentially leading to serious ABR infection. study found that same ABR-bacterial strain that colonized animals was found in infected humans (Enterococcus faecalis).
cross contamination
AMR in agriculture/aquaculture is highly interconnected, mainly thru ______.
cross-contamination (water system, irrigation, manure, plants, & livestock)
PBP enzyme function is to catalyze _____ reaction between the adjacent lipid II molecules between peptide side chains, by removing one of the alanines.
cross-linking
S. aureus resists vancomycin by overproducing peptidoglycan w/ decreased _____.
cross-linking
is the infection bacterial or viral? type of diagnostic test including blood, urine, stool, swabs - more time-consuming.
culture test
while bacteria can multiply every 20 min., _____ diagnostics can take a couple days. while bulky, expensive, & delicate equipment that require proper training is limited to healthcare settings, a lot of emphasis is being put on other _____ diagnostics methods that are being developed.
culture-based; rapid
isolated from Streptomyces; a D-alanine analog (inhibits 2 different steps of D-Ala-D-Ala synthesis); can penetrate membrane of gram (-) bacteria, thus acts as broad-spectrum antibiotic; restricted as secondary choice for (multidrug-resistant) MDR-Tb & (extensive-drug-resistant) XDR-Tb; inhibits D-alanyl-D-alanine synthesis.
cycloserine
synthesis of lipid II takes place in _____, where C-55-isoprenyl pyrophosphate flippase (a membrane protein).
cytoplasm
synthesis of _____ in bacteria requires series of steps: - GTP initially converted into dihydropterin pyrophosphate - then requires reaction catalyzed by enzyme dihydropteroate synthase in presence of p-aminobenzoate, which converts the 2 molecules into dihydropteroate. - dihydropteroate later converted into _____ by _____ synthase.
dihydrofolate (DHF)
essential enzyme for DNA synthesis in both prokaryotes & eukaryotes; however, substantial differences in structure of _____ in eukaryotes & prokaryotes, so it's possible to selectively inhibit either one w/ small molecules.
dihydrofolate reductase (DHFR)
type of point mutation/deletion/insertions that inhibits metabolism; mediated by a single amino acid substitution in _____ are enough to diminish trimethoprim binding.
dihydrofolate reductase (trimethoprim)
DHF synthesis requires _____ & _____.
dihydropterin; PABA
gene that Forsberg isolated from soil bacteria: sul1, which encodes for highly resistant variant of _____; this type of resistance to sulfa drugs is mediated by target modification.
dihydropteroate synthase (DHPS)
type of point mutation/deletion/insertions that has plasmid-encoded sul1 & sul2 genes, which confer resistance to sulfonamides; highly effective at dissemination among bacteria; sul1 & sul2 genes code for a highly resistant variant of _____ enzymes that catalyzes a condensation reaction between PABA & dihydropterin pyrophosphate into dihydropteroate.
dihydropteroate synthase (sulfonamide resistance)
type of antibiotic target modification that concerns point mutations/deletions/insertions includes?
dihydropteroate synthase; dihydrofolate reductase; DNA gyrase & topoisomerase IV; & RNA polymerase
enzymatic degradation is a type of antibiotic inactivation; it can be done thru either _____ or _____.
hydrolysis or linearization
B-lactamases are enzymes that _____ B-lactam antibiotics.
hydrolyze
type of enzymatic modification (type of antibiotic inactivation); involves addition of hydroxyl (-OH) group).
hydroxylation
certain medical conditions can make any of us lose battle against bacteria by suppressing ability of our _____ to defend our bodies against invaders.
immune system
complex interactions between organs/ tissues, & different body parts.
immune system
spread of antibiotic resistance: community exposed to ABR, pathogenic bacteria; many can & will be colonized w/o symptoms until conditions are appropriate. these conditions could be?
immunosuppression; secondary infection; or use of antibiotics.
finally, antibiotics can select for mutations that change the structure of the porin channel rendering them ____ to antibiotics.
impenetrable
antibiotics are classified as ______ if the antibiotic meets neither WHO criterion 1 nor criterion 2.
important
type of screening platform called culturing the "unculturable": methods of _____ followed by domestication will enable drug discovery from this previously inaccessible source.
in situ cultivation
type of vaccine in which the pathogen has been killed.
inactive vaccines
weakening/inactivation of pathogen in both types of vaccines ensure that the pathogens don't develop into the full-blown disease; like disease, they trigger immune response teaching body to recognize attack. downside of inactive vaccines: don't create long-lasting immunity.
inactive vaccines
does antibiotic prophylaxis really work? in U.S.: 3 studies (2 showed no change, 1 showed _____ in infective endocarditis (IE) but design had flaws).
increase
in E-test, w/ concentration gradient increasing for any of these antibiotics, zone of inhibition for S. aureus _____. MIC is concentration of antibiotic required to completely inhibit bacterial growth; so, what we see is that 2 micrograms/mL of _____ starts to completely inhibit growth of S. aureus on that plate. for daptomycin, MIC is about _____ micrograms/mL. for linezoid: _____ micrograms/mL.
increases; vancomycin; 1.0; 1.5
growth rate decreases, but population is still rapidly?
increasing
____ expression is the stimuli for efflux pumps.
inducible
the regulation of efflux pumps costs cell a lot of energy, so ____ is useful in this regard.
induction
low concentrations of antibiotics in healthcare, agriculture, & environment or the low concentrations of antibiotics we consume in meat products; animals/humans exposed to in water; low concentrations of antibiotics of an unfinished dose/underdose. these all demonstrate what?
induction of antibiotic resistance
many common treatment options for bacterial infections are becoming _____ across parts of the world.
ineffective
cheaper alternative to hygiene maintenance thru antibiotics?
infection control
PACCARB recommends expand, standardize, & improve delivery of _____ & _____ education/training at all levels of the healthcare workforce.
infection prevention; antibiotic stewardship
if we could find a way to boost immune system to point that bacteria would be eliminated before they get chance to progress to _____, we could decrease use of antibiotics & reduce _____.
infection; ABR
does antibiotic prophylaxis really work? France: no increase in _____, but studies had flaws.
infective endocarditis (IE)
estimated that undiagnosed STDs cause _____ in more than 20k women each year.
infertility
deaths related to _____ are highest early in life & later in life.
influenza
discovery of B-lactamases triggered the scientific community to pursue identification of compounds that would _____.
inhibit B-lactamases
1st step of bacterial translation; components required for protein translation come together: ribosomal subunits, tRNA, & mRNA; first AA attached to tRNA.
initiation
ability of body to respond to infections provides protection better than any antibiotic ever made: _____ & _____.
innate & adaptive immunity
_____ composed of specific cells that allow rapid detection/response to invading pathogen; happens in matter of minutes-hours.
innate immunity
immediate response allows body to react quickly as invader detected. composed of cells that can rapidly respond to invading pathogens by mounting antimicrobial responses.
innate immunity
treated wastewater effluent can contain variety of ABR bacteria & ARG's, including high levels of class 1 _____.
integrons
many of the identified host-directed antimicrobial drugs are effective against other _____ pathogens.
intracellular
bacteria that cause STDs are known as ____ - they hide within human cells & are almost undetectable by our immune system; once they infect the host, they will stick around for a while.
intracellular pathogens
targeting host resources required for survival of _____ bacteria. e.g., _____ requires cholesterol at plasma membrane in order to carry out proper infection cycle. treating human macrophages w/ each of these compounds (62 different FDA-approved drugs that sequester cholesterol from plasma membrane) almost completely inhibited infection by _____. results demonstrated that targeting _____ can inhibit infection.
intracellular; Coxiella; Coxiella; host resources
2 major types of ABR?
intrinsic & acquired
bacteria naturally resistant to certain antibiotics. e.g., outer membrane of gram-negative bacteria makes them more resistant to more antibiotics than gram-positive bacteria
intrinsic ABR
antibiotics also much less effective against oral biofilms, why?
intrinsic ability of biofilms to resist antibiotics & other antiseptics.
gram (-) bacteria are one of the most dangerous types of pathogens, why?
intrinsic ability to resist antibiotics combined w/ their mechanisms of antibiotic resistance
bacteria that naturally produce antibiotics need to be _____ to these antibiotics; otherwise, they would be deemed for self-destruction.
intrinsically resistant
at periplasmic space, C-55-isoprenyl pyrophosphate flippase releases _____, which is then incorporated into growing peptidoglycan structure & cross-linked by PBP; C-55 is then recharged & flips back across membrane into cytoplasmic portion.
lipid II
final intermediate of peptidoglycan biosynthesis, N-acetylmuramic acid pentapeptide, fuses w/ N-acetylglucosamine (called _____, when fused together).
lipid II
as defense mechanism against antibiotics, bacteria also secrete proteins including ____, & it could also secrete other small molecules such as _____ that both of the membranes & molecules bind & sequester antibiotics including polymyxins, rifamycin, daptomycin, etc.
lipocalins; monomeric phosphatidylglycerol
amphipathic molecules that're attracted by negatively charged phospholipids on bacterial membranes.
lipopeptides
characterized by a peptide ring attached to a fatty acid side chain; hydrophobic fatty acid chain is thought to penetrate & disrupt lipid bilayer; this structure = rich in non-proteinogenic amino acids, namely 2,3-diaminobutyrate; diaminobutyrate are protonated at physiological pH, giving molecule strong positive charge.
lipopeptides
class of antibiotics that disrupts the cell membrane by poking holes in bacterial membranes. e.g., polymyxins & daptomycin.
lipopeptides
cell-membrane-disrupting antibiotics?
lipopeptides & isoniazid
artificial membrane-bound vesicle that captures bacterial toxins & titrates them out from acting directly on the host cell membrane.
liposome-based cytotoxin inhibitors
made of pathogen itself but much weaker/tamer version. downside: difficult to make & dangerous for those w/ weakened immune systems, like the elderly.
live, attenuated vaccines
looked at effect of exercise on infection of Salmonella in murine models; one group was sedentary, & one was active (30-minute swim exercise); 2 groups were both infected, & bacterial loads were quantified in stool, liver, spleen, & Peyer's patches; exercised group had _____ bacterial load in fecal pellets & in all organs; almost undetectable levels of Salmonella in _____ & _____.
lower; liver; spleens
some antibiotics penetrate slowly or cannot penetrate biofilms at all due to _____.
electrostatic repulsion
6th step of bacterial translation; ribosomes continues to move along mRNA & new AA's are added to growing polypeptide chain.
elongation
when Griffith injected mice w/ virulent strain that had intact capsule (encapsulated); all mice died. bacteria isolated from dead mice were all ____.
encapsulated
gram-negative are more resistant to antibiotics, because their outer membrane comprises a complex LPS, whose lipid portion acts as an _____; develop resistance sooner as well.
endotoxin
was previously known that plasmid-mediated resistance to tetracyclines requires _____, & it's not dependent on antibiotic degradation. therefore, it was suspected that other mechanisms must be involved.
energy
includes activation of pathways that generate reactive nitrogen species, reactive oxygen species, proteases, degradative proteins, & antimicrobial peptides.
enhance human cells to kill bacteria.
____ & ____ ecosystems represent reservoirs that are source of ABR in clinical ecosystem.
environmental & non-clinical
microbes encounter low concentrations of antimicrobial compounds, perhaps produced by other microbes, but not as much as clinical antibiotics; also known as resistome, because every single antibiotic-resistant gene is present in that environment but not selected for.
environmental (natural) ecosystem
exhibits low selection for ABR; contains natural antibiotics; all ABR genes are present here, & it's likely that ABR originated in this ecosystem & spread to other 2 by increase of selection pressure.
environmental ecosystem
selection pressure for antibiotic resistance is explained by 3 microbial ecosystems. what are they?
environmental ecosystem, non-clinical ecosystem, & clinical ecosystem
to date, there are 4 different mechanisms by which bacteria become resistant to tetracyclines. one is by ____, the other 2 are by ____, & the last one is by _____.
enzymatic activation; target modification; active efflux out of cell
3 ways of antibiotic inactivation?
enzymatic degradation, enzymatic modification, & antibiotic inactivation by sequestration
biochemical modification of antibiotics that increases steric hindrance; as a result, the antibiotic loses its ability to recognize targets, & the MIC increases.
enzymatic modification
emerging method for analyzing ARG's; generic method for linking 2 genes, originating from one cell to one amplicon, which can be sequenced.
epicPCR
23S rRNA mutations of 50@ (MLSB) post-translational modification: _____ genes code for adenine-specific N-methyltransferases that catalyze ribosomal methylation. erm genes are encoded on ____ (mobile elements that can easily transfer) across both gram (-) & gram (+) bacteria.
erythromycin ribosome methylation (erm); plasmids
plant-derived drug isolated from wild Mandrake, common in eastern U.S.
etoposide (cancer chemotherapeutic agent)
where did ocean AMR come from in terms of marine origin?
evolution & aquatic life (as excretion from aquatic animals)
_____ enhances the immune system: evidence from animal studies. example: looked at effect of exercise on infection of Salmonella in murine models.
exercise
to combat biofilm infections: Pseudomonas fluorescence first grows a biofilm, then degrades it by producing a specific _____ that leads to release of cells from matrix - could be a pathogenicity mechanism. understanding details of such self-destruction would allow to identify additional ways to induce biofilm self-destruction.
exopolysaccharide lyase enzyme
B-lactamases that are derived mostly from modification of TEM-1 or TEM-2 & SHV-1 B-lactamases.
extended-spectrum B-lactamases (ESBL)
soil can become contaminated by ABR from?
farms
human gut microbiota involved in what processes?
fat metabolism, tissue regeneration, regulation of immune system, function of nervous system, digestion, bone density & others. production of many biologically active molecules including metabolites, cofactors, nutrients, & unknown others.
is the infection bacterial or viral? differentiated based on empirical evidence such as?
fever, past history, environment, & predisposition
number of ways in which a counterbalance to ABR can be approached; discovering new ways to combat ABR either thru _____, _____, & _____.
finding new antibiotics, enhancing function of antibiotics, & targets mechanisms of ABR
addition of _____ atom @ position 6 of quinolone bicyclic ring greatly enhanced antimicrobial activity, making fluoroquinolones a broad-spectrum bactericidal antibiotic.
fluorine
in July 2018, FDA ordered pharmaceutical companies to add warning labels to their _____ drugs.
fluoroquinolone
Mycobacterium ____ expression in M. tuberculosis leads to fluroquinolone resistance.
fluoroquinolone resistance protein A (MfpA)
_____, in 1990s, were used to treat gonorrhea; however, bacteria adapted to drugs.
fluoroquinolones
in 2000, _____ are no long recommended to treat people w/ gonorrhea in Asia or Pacific Islands, & by 2002, this recommendation extends to CA.
fluoroquinolones
humans cannot synthesize _____ (aka vitamin B9), making it a good target for antibiotics.
folate
nearly 80% of all antibiotics are used in _____, so selection process is stronger in animals than humans.
food animals
·major sources of resistance = bacterial hosts exposed to a selective pressure that allows them to develop ABR; hosts include?
food animals, humans, & pets
because population still increasing, there are issues w/?
food supply
isolated from streptomyces; highly reactive epoxide ring w/ broad-spectrum bactericidal properties; enters cell via hexose monophosphate transporter/glycerophosphate transporter; inside cytoplasm, irreversibly inhibits early steps of bacterial cell wall biosynthesis in bacterial cytoplasm - inhibits MurA.
fosfomycin
cloning & expression of environmental DNA in a lab host can overcome limits of PCR & metagenomic sequencing in detecting mostly known resistance genes.
functional metagenomics
reporting to GLASS: _____ is still an issue, but hopefully, better mechanisms will be developed to allow lower-income countries to increase reporting rates.
funding
metal that's effective at killing P. aeruginosa; can substitute for ion leading to disruption of iron homeostasis; approach especially important for cystic fibrosis patients & burn victims.
gallium
when Griffith injected mice w/ heat-killed, encapsulated & live, non-encapsulated bacteria; all mice died. bacteria isolated were all encapsulated. how?
genetic material from dead bacteria was picked up by live bacteria that were originally capsule-deficient.
_____ between bacteria of same species hinders vaccine _____ & will lead to resistance as well.
genetic variation; specificity
genome sequencing methodology used to predict targets & employed large-scale screens for novel antibiotics.
genome high-throughput screens period
relatively less side effects than other aminoglycosides; has rapid bactericidal activity & is therefore, commonly used to treat eye infections.
gentamicin
AMR is one of the biggest threats to _____ & _____ today.
global health & food security
global solutions to AMR?
global regulation (putting a cap), meat consumption reduction, & user fees (deduced to be first & best option)
class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides; non-B-lactam cell wall synthesis inhibitors that cap D-Ala-D-Ala & prevents its incorporation into peptidoglycan & subsequent crosslinking; only effective against gram (+). e.g., vancomycin (effective against MRSA)
glycopeptides
to combat biofilm infections: _____ secreted by biofilm producers are capable of degrading exopolysaccharides, & therefore, provide a potential candidate substance that has capacity to destroy biofilms; relatively new discovery, so still not used in clinical settings yet.
glycoside hydrolases
type of enzymatic modification (type of antibiotic inactivation); involves attachment of a carbohydrate/sugar.
glycosylation
marked discovery of all major classes of antibiotics.
golden era
drug resistance, especially _____, is a major threat to reducing impact of STDs worldwide.
gonorrhea
earlier this year, 2 cases of this extensive drug-resistant _____ reported in U.K. hasn't been detected in U.S. yet, but high transmissibility & high selection w/ antibiotics makes emergence of this superbug inevitable.
gonorrhea
easy transmission of ____ also allowed for diversification of resistance mechanisms.
gonorrhea
major public health concern in U.S.; more than 800k new infections occur each year, but because many people don't have symptoms, fewer than half are detected/reported to CDC.
gonorrhea
there are about 1/3 less cases of ____ than chlamydia, but chlamydia is fully curable. ____ rapidly gaining resistance to all antibiotics.
gonorrhea
regarding ____ infections: # of total bacterial infections in U.S. & the resistance is increasing.
gonorrheal
_____ bacteria produce very aggressive types of B-lactamases, bc they can secrete them into extracellular space if they sense presence of antibiotics, & they could inactivate antibiotics even before they can reach their target.
gram-negative
do not retain violet dye; stained red/pink.
gram-negative
least sensitive strains to penicillin?
gram-negative bacilli
in _____, peptidoglycan layer is thinner & located in periplasmic space between inner plasma membrane & outer membrane.
gram-negative bacteria
can be in clusters (e.g., S. aureus); can be in chains (e.g., S. pneumoniae); or can be found in tetrads (e.g., Micrococcus).
gram-positive cocci
bacteria/antibiotics from humans & pets enter water systems thru?
ground & wastewater
in 2017, the FDA banned use of antibiotics as _____.
growth promoters
in 1990s, fluoroquinolones became treatment of choice for gonorrhea, but these rapidly became useless due to these point mutations in ____ & ____.
gyrA & parC
flluoroquinolones inhibit DNA replication; eukaryotic DNA packaged around histones, whereas gyrases packages DNA into supercoils in bacteria; thus, targeting bacterial _____ doesn't interfere w/ human DNA.
gyrases
PACCARB recommendation #2: highlights _____ in curricula at all levels of training as foundational requirement for successful infection prevention; recognizing & applying successful tactics for achieving high-_____ compliance in healthcare settings.
hand hygiene
according to PACCARB, _____ & _____ are best defense during flu season.
hand sanitizers & hand soap
most serious gram-negative infections are _____-associated.
healthcare
serious antifungal resistant strains of candida have been emerging, making candida the leading cause of _____ in U.S. hospitals.
healthcare-associated bloodstream infections
patients w/ underlying _____ condition or those who have _____ may require antibiotics prior to dental procedures, because dental procedures can induce infective _____.
heart; prosthetic joints; endocarditis
underlying conditions (i.e., diabetes, genetics, etc.): example of genetic condition - _____, which leads to iron overload & allowed patient to grow _____ in his body, which is not typically a pathogen that infects human.
hemochromatosis; Yersinia pestis
extracorporeal filters that clear blood pathogens by their physiochemical property.
hemoperfusion devices
used in agriculture to control growth of weeds that interfere w/ crop growth. e.g., Waterhemp, which has developed resistance to many commercially available herbicides.
herbicide
agri-/aquaculture (farm & aquatic animals) has _____-selection pressure.
high
according to WHO prioritization of antibiotics, if drug meets 2/3 the prioritization criteria, it's marked at _______.
high priority
type of screening platform; not all drugs penetrate bacteria (e.g., vancomycin is only effective against gram-positive, since outer layer of cell wall of gram-negative bacteria is impenetrable by vancomycin, & vancomycin is too large too pass thru gram-negative bacteria's porins).
high-throughput screening (HTS)
according to WHO prioritization of antibiotics, if drug frequently used; prone to induce resistance; & is targeted at prevalent zoonotic disease, then antibiotics prioritized at _____.
highest priority
antibiotics are classified as _____ if they meet either WHO criterion 1 OR criterion 2.
highly important
ESKAPE pathogens have ability to transfer/accept genetic material from other sources; become ____ to many classes of antibiotics.
highly resistant
antibacterial activity between different types of _____ can vary by 100-fold; only food that has no expiration date.
honey
has been successfully used as wound-dressing for thousands of years.
honey
lateral gene transfer defined by transfer of genetic material between organisms; can be mediated 3 different mechanisms: transformation, transduction, & conjugation.
horizontal gene transfer
mecA gene located on mobile element called a Staphylococcal cassette chromosome mec (Sccmec) whose intra- & interspecies mobilization can be facilitated thru _____; these jumping genes allow mecA to quickly spread throughout clinical strains.
horizontal gene transfer
wastewater treatment plants can served as hotspots for _____, enabling spread of ABR genes between different bacterial species.
horizontal gene transfer.
ESKAPE pathogens are found ubiquitously, & overuse of antibiotics selected for the resistance that is most often linked to ____ settings. many of these strains grow rapidly; infections by these pathogens also have rapid onset.
hospital
antibiotic resistance increases average _____ & _____.
hospital stay & mortality
no known CA-VISA/VRSA. VISA/VRSA are exclusively ____.
hospital-acquired
most deaths related to AMR occur as?
hospital-acquired infections
HA-MRSA stands for _____ MRSA.
hospital-acquired/associated
ESKAPE pathogens are highly transmissible - nearly impossible to eliminate from ____.
hospitals
recent evidence suggests that ____ also affects gene transfer between bacteria; seems as if humans unintentionally are largest source of diversity of acquired ABR.
host
targeting the _____ to inhibit bacterial infections is a promising approach alternative to antibiotics; can also be used in combination w/ current antibiotics or molecules that target bacteria.
host
_____ exhibit a broad-spectrum efficacy in inhibition of intracellular bacterial pathogens.
host-directed antimicrobials
drugs that prevent/treat infection by targeting host cells.
host-directed antimicrobials
____ carry ABR; resistance genes are especially present in commensal, strict anaerobic bacteria that aren't pathogenic to humans; ARGs are also acquired from neighbors or bypassing microbes.
human gut microbiome (also include oral & vaginal microbiota)
AMR occurs naturally, but misuse of drugs in ______ & _____ is accelerating the process.
humans & animals
type of enzymatic degradation (type of antibiotic inactivation); involves destruction of B-lactam antibiotics by B-lactamases.
hydrolysis
while antibiotics can kill planktonic cells, cells embedded in biofilm are resistant & can represent more diverse metabolically inactive body of cells, including SCV, which stands for _____, & the biofilm cells that excrete exopolysaccharides.
small cell variant persister cells
_____ was wiping the population of earth as soon as it appeared until no other victims were able to carry it.
smallpox
doctors took small samples of scabs from _____ patients, ground it into a fine powder, & blew it into the noses of healthy individuals. Arab physicians used a similar approach, where they'd make a small incision into person's skin & rub a wound swab from a _____ patient. in both cases, people became immune to _____.
smallpox
according to PACCARB, _____ gets more viruses; should wash for a full 20 seconds.
soap
_____ has highest density of bacteria, & majority of bacteria in _____ aren't culturable in lab conditions.
soil
_____ provides one of the most complex microbiome environments.
soil
lowest antibiotic selection pressure but contains largest diversity of ABR genes.
soil
provides one of the most diverse microbial environments; however, it's estimated that 99% of all _____ bacteria aren't culturable in lab.
soil
these bacteria hold potential to combat ABR; however, in order to tap into that potential, scientist need proper funding/resources. discovery process is much slower than process of ABR, & this is the big issue.
soil
while antibiotics are rapidly excreted from human body & don't get chance to get degraded, in ____, they remain for longer periods of time.
soil
Forsberg identified 16 sequences of ABR genes isolated from ____ - were 100% identical to ABR genes isolated from infections in diseased human hosts.
soil bacteria
how do ABR travel thru liquid droplets/solid particles?
soil, leaves, organic matter, water, human & animal fecal matter, wastewater, & composting facilities
AMR reservoirs w/ low-selection pressure?
soil, water (oceans), & human microbiota (i.e., gut, oral)
characterized by macrocyclic lactone connected to sugar moiety via glucosidic bonds; isolated from soil actinobacteria, Saccharopolyspora (e.g., erythromycin, clarithromycin, & azithromycin); high affinity for 50S ribosomal subunit, where actually bind to same site as lincosamides; bind to proximal end of peptide exit tunnel, thru which nascent polypeptide chain grows & consequently, inhibits peptidyl transferase from adding additional AA's to growing polypeptide chain.
macrolides
nascent peptide exit tunnel (NPET)-targeting antibiotics are? *inhibited by bacterial ATP-binding cassette F (ABC-F) ribosomal protection protein.
macrolides & streptogramin B
host-directed antimicrobial therapy @ cellular level: targets individual cells (i.e., _____).
macrophages
under normal conditions, _____ metabolize glucose thru glycolysis & end product is _____ that enters TCA cycle in mitochondria.
macrophages; pyruvate
plant-derived drug isolated from poppy plants.
morphine (analgesic)
_____ increased threefold for VRE as opposed to VSE.
mortality rates
lysinylation: TCRS controls expression of _____; resistance regulated by a 2-component histidine kinase regulatory system, where daptomycin is sensed by sensory kinase, which phosphorylates & activates the regulatory that induces the expression of the ____ gene, which in turn adds lysines to phospholipids; induction of the _____ gene leads to elevated levels of MprF that adds lysines to phospholipids.
mprf
this class of membrane efflux pumps is powered by a sodium gradient.
multi-drug & toxic exclusion (MATE)
porins & efflux pumps confer _____.
multi-drug resistance (MDR)
intrinsic antibiotic resistance combined w/ acquired resistance gives rise to _____ superbugs.
multi-drug resistant (MDR)
targets tRNA; it's a CA from Pseudomonas fluorescencs; non-ribosomal translational inhibitor; binds to & inhibits isoleucyl-tRNA synthetase; concentration-dependent bactericidal; quickly metabolized when received orally or intravenously; restricted to topical applications (Bactroban) only.
mupirocin
tRNA antibiotics?
mupirocin & puromycin
covalent polymer that composes strong part of bacterial envelope, w/ exception of a few bacteria such as mycoplasmas.
murein (peptidoglycan)
split of Archaea & Eukarya happened after bacteria murein wall development & led to different solutions to same osmotic problem bacteria faced. how did bacteria solve this problem?
murein sacculus
____ known as lipid II; function as major triggers of Amp-GRC pathway. once liberated from peptidoglycan, ____ are transported into cytoplasm by Amp-G transporter.
muropeptides
____ in efflux pumps render bacteria 10-100 times more sensitive to antibiotics.
mutations
in isoniazid: activated isonicotinic acyl-NAD binds to & activates enoyl acyl carrier protein reductase that's responsible for synthesis of _____ (major component of Mtb cell wall).
mycolic acid
type of antibiotic that kills specific organism; prescribed when the bacteria is known.
narrow-spectrum
lots of "alternative medicine," but do they work? _____ possess antimicrobial properties, but if you develop a serious infection & no access to antibiotics, there's little that will help; & these home remedies/alternative therapies can quickly make things worse. can take steps to enhance _____, however.
plants; immune system
in conjugation (HGT), donor cell carries _____ while recipient doesn't; donor cell is known as fertility factor (F positive), while recipient is _____.
plasmid; F negative
_____ diagnostics: - performed at/near patient: portable. - rapid turnaround time. - provides actionable info that contributes to patient's wellbeing.
point-of-care (POC)
rapid diagnostic methods: many of these are so-called _____, meaning they can be used at or near patients, which makes them more portable/convenient to use. while there are a number of _____ devices on market that can detect specific bacteria, a device that will detect ABR is still yet to be developed.
point-of-care (POC) diagnostics
opsonize bacteria by binding to them & making them more visible to the immune system.
polyclonal/monoclonal antibodies; immune adjuvants
from Bacillus polymyxa; successfully used against gram (-) bacteria due to their neurotoxic & nephrotoxic effect - replaced by sager antibiotics; prevalence of "superbug," mainly Acinetobacter baumannii, Pseudomonas aeruginosa, & Klebsiella pneumoniae prompted return of _____ clinical use.
polymyxins
peptide antibiotics that target bacterial cell membrane; wide-spread antibiotic resistance among gram-negative bacteria leaves _____ as last-reserve antibiotics.
polymyxins
2 types of lipopeptides?
polymyxins & daptomycin
in B-lactamase testing, more specifically modified hodge test (MHT), _____ produces B-lactamases, which degrades carbapenem antibiotic & allows indicator strain to grow in the zone of inhibition.
positive control strain (streaked out from center of plate, #1)
a screen platform approach in which new drugs are discovered based on designing a molecule that's predicted to bind its target based on charge & shape complementation.
rational design
in transduction, as virus injects DNA that contains parts o donor bacterial genome, the DNA can get incorporated into recipient cell by _____. result: virus carried genetic material from onto cell into recipient cell.
recombination events
8th step of bacterial translation; last tRNA released, & ribosomes come apart; released polypeptide forms new protein.
recycling
some evidence of transduction comes from sequencing of DNA from phages that were isolated from ____, ____, & ____; found that phage DNA containing ABR genes identical to those found in bacterial clinical isolates. e.g., extended-spectrum B-lactamases, variants of PBP2a, quinolone-resistant genes were found in phage DNA.
sewage, river waters, & fecal polluted waters
in conjugation (HGT), donor attaches to recipient cell via _____, which draws cells together; then, one strand of plasmid DNA transfers to recipient cell, which then synthesizes complementary strand to become _____; donor cell also synthesizes complementary strand to restore its complete plasmid.
sex pilus; F positive cell
early screening for Tb drugs identified mainly _____ drugs.
species-specific
this type of screening platform looks for antibiotics against a specific pathogen, which is more effective than screening for compounds that inhibit general bacterial growth.
species-specific compounds
why is isoniazid the most commonly used antituberculosis drug?
specifically inhibits the synthesis of mycolic acid.
binding of aminoglycosides to 30S ribosomal subunit leads to inhibition of _____ from A to P site & causes misreading of mRNA; can compromise protein stability - leads to aggregation; loss of function; & misfolding. for essential proteins, this means death.
tRNA translocation
gonorrhea has picked up resistance thru ____, ____, ____, ____, & ____.
target replacement, target protection, target modification, efflux, & inactivation of antibiotics
solution to immunosuppressing medical conditions that make bacterial infections harder to fight?
target the host to enhance immune system
serious ADR's for fluoroquinolone antibiotics? *Cipro, Levaquin, Avelox, & all fluoroquinolone antibiotics.
tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, permanent pain syndrome, crippling side effects in health individuals, & exacerbation of myasthenia gravis.
hexagonal unit of wall area composed of 2 nonamuropeptides linked to each on both sides by chains of disaccharides muropeptides: one points up from wall plane, one points down, & one points outward from _____ & is part of another _____.
tessera
Clinical Laboratory Standard Institute (CLSI) creates a sort of _____; constantly monitors test quality to ensure optimal patient care.
test standardization
after being turned on once tetracycline has bound to tetR, ____ begins to transport tetracycline out of cell by tightly regulating inducible expression of tetracycline efflux system; cell able to conserve energy.
tetA
upon cellular entry, tetracycline binds ____, which leads to conformational changes that allow the release of ____from promoter regions. as a result, _____ & tetA genes are turned on.
tetR
enzymes that degrade tetracycline antibiotics (similar to B-lactamases that destroy B-lactam antibiotics).
tetracyclince destructases
in 16S rRNA mutations of 30S, _____ overlaps partially w/ the aminoacyl-tRNA binding site leading to tRNA dissociation from the ribosome consequently blocking translation.
tetracycline binding site
antibiotics that target translation at the 30S ribosomal subunit; family of antibiotics that inhibit protein synthesis by preventing the attachment of aminoacyl-tRNA to the ribosomal acceptor (A) site; broad-spectrum agents, exhibiting activity against a wide range of gram-positive and gram-negative bacteria.
tetracyclines
class of antibiotics that target protein synthesis of 30S subunit. Isolated from soil-dwelling bacteria, Streptomyces; broad-spectrum antibiotic effective against gram-negative gram-positive, intracellular bacteria (rickettsias & chlamydias); may even wipe away good human microbiota, predisposing patients to fungal infections & induce gastrointestinal problems. e.g., doxycycline, lymecycline, & oxytetracycline.
tetracyclines
antibiotics that can cause photosensitivity?
tetracyclines, quinolones, & sulfonamides
basic unit polymerized outside cytoplasmic membrane that forms the individual tessera & the sacculus cell covering.
tetrasaccharide nonamuropeptide
used to reduce use of antibiotics: 10-million-pound prize fund w/ an 8-million-pound payout that will reward a competitor that can develop a POC diagnostic test that will conserve antibiotics for future generations & revolutionize the delivery of global healthcare; the test must be accurate, rapid affordable & easy to use anywhere in world.
the Longitude Prize
certain drugs are still administered at toxic concentrations; this decision made on individual basis; the benefits of administering toxic drug must outweigh risk associated w/ infection. such cases are reserved to extreme instances, where bacteria become resistant to every single line of antibiotic; little alternative options. t/f?
true
concentrations of antibiotics, bacteria, & resistance genes can be spread thru wind, t/f?
true
constant exposure of bacteria to sublethal concentrations of honey did not result in resistance. t/f?
true
efflux pumps are predominantly present in gram (-) bacteria, t/f?
true
exposure of humans to environmental bacteria boosts immune system, especially in developing/growing children. t/f?
true
famous 2009 publication in Clinical Infectious Diseases, IDSA states that it "continues to view w/ concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram (-) pathogens." t/f?
true
fluoroquinolones are severely toxic to humans, t/f?
true
generally, all antibiotics affect human microbiota. t/f?
true
gonorrhea resistance: isolates from 7 patients in HI were resistant to azithromycin, & 5 of them began showing resistance to cephalosporin. t/f?
true
in presence of low concentration of tetracycline, Salmonella typhimurium rapidly developed resistance. t/f?
true
increased mortality is a consequence of AMR, t/f?
true
limiting exposure to microbes dampens the immune system, t/f?
true
microbes not only secrete anti-antibiotic molecules, but they also develop clever ways to counter effect of antibiotics. t/f?
true
most antibiotics are naturally produced, t/f?
true
neither Teixobactin nor Odilorhabdin made it to clinical trials yet & even if they do, 90% of drugs fail, t/f?
true
not every bacterial species is inhibited equally be penicillium, t/f?
true
number of infections in general remains more or less the same, but number of AMR infections has been constantly increasing. t/f?
true
ocean is packed w/ complex microbial communities, t/f?
true
outer cells of biofilm formation absorb all the damage from antibiotics, & they protect the cells that sit deeper within the biofilm. t/f?
true
report on infection resistant to all known antibiotics came out late March 2018 from England's public health agency; described case of gonorrhea resistant to both components of dual-antibiotic therapy of azithromycin & ceftriaxone - the only remaining recommended treatment for gonorrhea. t/f?
true
soil is largest known reservoir of ABR genes. t/f?
true
some of these biofilms may also contain protozoan organisms, nematodes, & rotifers, t/f?
true
surveillance is neither coordinated nor harmonized. t/f?
true
there are many gaps in info on pathogens of major public concern. t/f?
true
there are some cases of persistent & drug-resistant chlamydia, but most are curable w/ current antibiotics. t/f?
true
unlike in clinical setting, soil is not taken over by ABR-bacteria. t/f?
true
penicillin can be used to isolate penicillin-insensitive pathogenic microbe that grows w/ & is masked by other microbes that are penicillin-sensitive, t/f?
true e.g., can isolate B. influenzae
TCRS-controlling B-lactamase Synthesis result: BlaR1 cleaves itself & becomes an active protease. BlaI leaves promoter from BlaZ, & BlaZ expression is?
turned on
form of resistance results from conjugal transfer of plasmid that contains vanA operon, that codes for number of genes whose products are responsible for substituting alanine for lactate in D-Ala-D-Ala dipeptide.
vancomycin resistance (vanA operon) migration thru conjugal transfer
rapid development of _____ curbed use of vancomycin against MRSA w/ fear that if MRSA becomes resistant to vancomycin, resistance could quickly spread & lead to pan-resistant strains of S. aureus.
vancomycin-resistant Enterococci (VRE)
some 30 years after into to vancomycin into clinical use, new superbug emerged called _____ & enterococci (VRE).
vancomycin-resistant stapylococci (VRS)
studies showed that vancomycin-resistant enterococcus (VRE) infection resulted in a 17-day hospital stay, as opposed to 3 days for _____.
vancoymcin-sensitive strain (VSE)
most important diagnostic tool in prescribing antibiotics is one that tells difference between _____ & _____ infection w/o making assumptions.
viral & bacterial
weaken immune system leading to opportunistic bacterial infections; antibiotics sometimes given to those w/ _____ as a prophylactic measure against more serious bacterial infections such as bacterial pneumonia.
viral infections
transduction is?
virally mediated
bacteria are less likely to develop resistance to drugs that target _____ as opposed to drugs that target fitness.
virulence
this screening platform focuses on inhibition of virulence factors in combination w/ antibiotics; this method can battle infection or allow clearance by immune system.
virulence factors
by _____, ocean AMR reservoir is larger than soil.
volume
release of ____ into oceans contributes to non-marine origin of ocean AMR.
wastewater
_____ & _____ can act as reservoirs & environmental supplies of antibiotic resistance.
wastewater; wastewater treatment plants
probably main source of all contamination, because main _____ reservoirs have cross contamination from nearby agriculture facilities that use antibiotics.
water
harbor large number of ABR genes.
water (oceans)
coastal water contamination is thought to originate from?
water runoff from agriculture
one of the most common source of biofilms are ____ or ____.
water towers or cooling towers
screening platform for species-specific compounds: _____ of resistant mutants can identify antibiotic targets.
whole-genome sequencing
aren't all bacteria inhibited by antibiotics if concentration is high enough?
yes, but limiting factor is the body: how much drug can we consume before it becomes toxic to us as well?
if antibiotics that are produced by the bacteria are toxic & will kill cell & only way to survive is when cell has intrinsic ABR mechanism in place (e.g., efflux pumps)... did these mechanisms exist before bacteria were able to make antibiotics?
yes, they must have; otherwise, cell would die.
____ account for nearly half of reported cases of chlamydia & face most severe consequences of an undiagnosed infection.
young women
diffusion method: based on spreading bacteria of interest on a culture plate, placing disks saturated w/ test antibiotic & allowing antibiotics to grow; antibiotic diffuses thru solid media creating _____ (similar to observation of Fleming on his mold-contaminated plate - penicillin discovery).
zone of inhibition
_____ is proportional to bacterial susceptibility to that specific antibiotic.
zone of inhibition *6 would be best to use, in this case.
each of these classes of antibiotics provides only treatment options against _____ bacteria that can easily gain resistance.
zoonotic
antibodies are commonly prescribed by physicians for prevention of...
§ HSV infection § Influenza § Rheumatic fever § Recurrent cellulitis § Meningococcal disease § Pertussis § Recurrent uncomplicated UTI § Spontaneous bacterial peritonitis in cirrhosis patients § Infective endocarditis § Acute necrotizing pancreatitis § Open fractures § Prosthetic joint replacement § Bite wounds
what kind of data is collected (in terms of specimen types) at each of the surveillance sites?
· Blood · Urine · Stool · Genital swabs
high-throughput screening (HTS): What are the requirements of Lipinski's "Rule of 5" Guidelines (in order for molecule to reach specific target in body)?
· MW < 500 Da. · H-bond donors < 5. · H-bond acceptors < 10. · octanol-water partition coefficient < 5. · molar refractivity should be between 40-130
best medium found for production of penicillin is _____.
ordinary nutrient broth
human gut microbiota is regarded as an additional ____.
organ
in China, people realized that _____ were immune to subsequent exposures of smallpox.
survivors
antibiotic surveillance on global level is an extremely challenging task. t/f?
true
as culture ages, antibacterial power of penicillin decreases & within _____ days @ 20 degrees C may have disappeared completely.
14
many _____ species are able to secrete large quantities of enzymes.
Bacillus
place on ribosome where first tRNA sits is.
P site
_____ tightly regulates the expression of mecA.
S. aureus
vancomycin penetrates ____ biofilms.
staph
mechanisms that govern intermediate resistance to ____ aren't understood.
vancomycin
in _____, Penicillin was called the "miracle drug" & became commercially available w/o prescription.
1943
_____ of species that reside in soil cannot be grown in lab, so it's hard to study these.
99%
where does AMR in HM come from?
agriculture; other individuals (i.e., caregivers); environment (less evidently)
U.S. households lost about _____ in 2000 to ABR-infections, due to extended hospital stays, premature deaths, & missed work.
$35 billion
urgent ABR threats in U.S.?
- C. difficile - carbapenem-resistant Enterobacteriaceae - drug-resistant Neisseria gonorrhoaea
what makes us prone to bacterial attack?
- age - underlying conditions - viral infections - physical trauma - medical procedures (surgeries, catheters, implants) - antibiotics - drugs (antifungals & immunosuppressants) - lifestyle (smoking, drinking, sleeping) - hygiene (poor vs. extreme) - diet (malnutrition)
5 classes of membrane efflux pumps?
- MDR & toxic exclusion (MATE) - major facilitator class (MFC) - small multi-drug resistance class (SMR) - resistance-nodulation-division (RND) - ATP-binding cassette (ABC)
factors contributing to AMR in healthcare?
- antibiotic usage (#1 problem) - lack of antibiotics - poor sanitation/personal hygiene - use of antibiotics in agriculture - inadequate infection controls in healthcare facilities
how does AMR occur?
- begins w/ some germs that are drug-resistant within a population - antibiotics kill bacteria, including human's natural flora - drug-resistant bacteria still survive & grow - surviving bacteria pass drug-resistance to other bacteria
consequences of AMR?
- leads to longer hospital stays. - higher medical sots. - increased mortality.
in presence of antibiotics, porins can undergo one of 3 major changes mediated thru acquisition of mutational resistance, they are?
- loss of porins - decreased expression of porins - narrowed porin channels
according to PACCARB, hands should take a full _____ to dry after hand sanitizer.
15 seconds
surveillance on AMR: data obtained from _____ members (out of 194 members); no standardized _____ methods; each country was asked to provide info on resistance _____ & date on a set of 9 antibiotics of public health importance; huge gap in knowledge & lack of capacity to collect national data on ABR.
129; detection; surveillance
by 2050, AMR is projected to kill _____ annually.
10 million
estimated that ~ _____ people carry S. aureus.
2 billion
_____ has a negative impact on outcomes for affected patients & healthcare expenditures.
ABR
bacterial resistance to antibiotics; first to observe the development of resistant bacterial strains.
Abramson & Chain
"re-discovery" of penicillin by _____ in 1928; plate infected w/ penicillium mold on accident & noticed bacteria (S. aureus, specifically) were not growing close to contamination source; area of inhibition around mold (except for E. coli & B. influenzae).
Alexander Fleming
first recommendations for handwashing were put forth by French chemist & pharmacist _____; developed sodium hypochlorite solution; showed antiseptic properties by neutralizing odor from decomposing human corpses; 80% of diseases are transmitted by touch; despite this number, only 40% of healthcare personnel adhere to hand hygiene.
Antoine-Germain Labarraque
biofilms 1st described/discovered in 1933 by _____, a bacteriologist: "it's quite evident that for the most part, water bacteria are not free-floating organisms but grow upon submerged surfaces"; after further examination w/ microscope, he noticed bacterial microcolonies.
Arthur Henrici
porins are transmembrane channels, usually _____, that allow molecules into cell.
B-barrels
14k people die each year in the U.S. from _____-induced diarrhea.
C. difficile
_____ infection can be caused by wiping out of good microbes in our gut thru use of antibiotics.
C. difficile
good bacteria that protect against infection are destroyed for several months when on antibiotics. this can lead to a _____ infection, picked up from contaminated surface or a healthcare provider's hands.
C. difficile
MultiLocus sequence typing revealed global transmission of ____. in one study, sequence typing was done on _____ strains, & it was revealed that there's a global distribution pattern between MRSA strains that travel/got transported between different countries/continents.
CA-MRSA
hand hygiene is so important, that _____ issues 56-page guideline on hand hygiene in healthcare settings.
CDC
population of 16 million; registered w/ 8 surveillance sites; has selected its National Reference Lab; has established its National Coordinating Center w/ National AMR Surveillance Plan; as of 2018, it has not deposited any data.
Cambodia
common fungus that lives in/on our bodies.
Candida
topo IV made up of ____ & ____.
ParC & ParE
initial interaction between PBP & methicillin happens at the active site thru a transient Michaelis complex followed by ____.
acylation
by 1950-1960's, ~ 80% of all clinical isolates of ____ strains were resistant to penicillin.
Staph
_____ also very sensitive to penicillin; slightly more than Staphylococcus.
Streptococcus pyogenes
innate immune responses also trigger second line of defense called _____.
adaptive immunity
product that accumulates in bacteria upon exposure to b-lactam antibiotics.
UDP-MurNAc-pentapeptide
what is ABR?
ability of bacteria to survive, & even thrive, in presence of antibiotics.
formation of vesicles, polymers, & catalysts occurred _____.
abiotically
most effective treatment against malaria; extracted from sweet wormwood.
artemisin
efflux pumps are used by bacteria in a variety of defense mechanisms that protect cells from their own antibiotics - one of the major ones is to quickly pump toxic antibiotics out of cell; employed to do what? e.g., Streptomyces export glucosyl-oleandomycin (inactive macrolide antibiotic) via OleB efflux pumps.
avoid toxicity from own antibiotics
in 2010: CDC takes additional measures to combat gonorrheal ABR, recommending dual treatment w/ either cefixime or increased dose of ceftriaxone & _____.
azithromycin/doxycycline
antibiotic sequestration: bacteria release _____, & these are released by both gram (-) or gram (+); these _____ bind to polymyxins & inhibit their membrane destroying property; in similar manner, presence of antibiotics (e.g., vancomycin) increases secretion of DNA by both gram (+) & (-) bacteria. then, DNA binds to vancomycin & it prevents its cellular entry.
capsular polysaccharides
_____ became commercially available in 1942.
penicillin
soil is regarded as _____ reservoir of antibiotic resistance.
primary
Hfr cells can then transfer genetic material to F negative recipient cells also thru conjugation; once in recipient cell, DNA recombines w/ genomic DNA of recipient cell, & cell becomes a recombinant but ______.
remains F negative
large reserve of diverse ABR genes that can lead to AMR in a clinical setting (pathogenic bacteria exposed to antibiotic selection).
reservoir of antimicrobial resistance
ARGs are highly mobile between ____.
reservoirs
bacteria develop _____ to antibiotics are able to replicate/survive in their presence. e.g., MRSA
resistance
type of antibiotic inactivation by ______; not really enzyme-dependent; the trapping of the antibiotic usually outside of the cell, preventing its entry & targeting its specific target.
sequestration
____ & ____ are the most common MRSA infection sites.
skin & soft tissue
ABR occur naturally in?
soil
combination of trimethoprim & sulfamethoxazole is commonly used in infections in severely immunocompromised individuals, such as HIV individuals; while bacteria develop resistance to trimethoprim, they're also able to develop resistance to sulfamethoxazole; sulfonamide resistance is mainly mediated by 2 highly mobile plasmid-encoded genes: ____ & ____.
sul1 & sul2
BHPS variants don't bind sulfonamides; therefore, bacteria that carry these genes are highly resistant to ____.
sulfa drugs
stimulate immune system to treat an already-existing disease (slow-progressing disease like cancer).
therapeutic vaccines
an enzyme that catalyzes dUMP to dTMP conversion.
thymidylate synthase
antibiotics responsible for ____ emergency visits for ADR events, & they're the most common cause of ER visits for ADR's in children under 18.
¼
greatest incidence of STDs is caused by 8 infections: they are?
- 3 bacterial (all "curable"): chlamydia, gonorrhea, & syphilis. - 4 viral (not curable): HBV, HSV, HIV, & HPV. - 1 parasitic (curable): trichomoniasis.
ARG's can be shared thru HGT facilitated thru...
- mobile genetic elements - transduction - transformation
host-directed antimicrobial therapy @ cellular level: targets individual cells (i.e., macrophages). methods include?
- modulation of bacterial entry. - limiting nutrients & resources. - enhancement of antimicrobial mechanisms.
characteristics of gram-negative bacteria?
- more resistant against antibiotics because of their impenetrable cell wall. - thin peptidoglycan layer (single-layered). - no teichoic acids. - periplasmic space present. - outer membrane present. - high LPS content. - flagellar structure: 4 rings in basal body. - produces primarily endotoxins. - mesosome less prominent. - more resistant to antibiotics.
currently, there are over ____ B-lactamases identified.
1,000
conversion of dihydrofolate to tetrahydrofolate is a 2-step reaction. what are the steps?
1. catalyzed by dihydrofolate reductase (DHFR); converts dihydrofolate back into tetrahydrofolate. 2. tetrahydrofolate further converted to methylene-tetrahydrofolate by serine transhydroxymethylase
estimated that the number of ADR's in hospitalized patients causes over ____ deaths annually.
100k
_____ countries provided data for at least 1 antibiotic.
114
2 large subunits of 80S ribosome in eukaryotes?
40S & 60S (made of ribosomal RNA & proteins)
ADR's are the ____ leading cause of death right after malpractice (100k-440k deaths).
4th
there are about _____ bacterial cells per tsp of ocean water.
5 million
antibacterial power of penicillin @ its max. in about _____ @ 20 degrees C; diminishes after 10 days until complete disappearance occurs @ 4 weeks.
7 days
name ESKAPE pathogens first appeared in an editorial commentary (_____) on antibiotic resistance crisis & a call for better deferral research funding to battle the problem.
Journal of Infectious Diseases
ESKAPE pathogen resistant to carbapenemases (last-reserve antibiotics).
K. pneumoniae
ESKAPE pathogen that has carbapenem-hydrolyzing B-lactamases (Klebsiella pneumoniae carbapenemase, KPC-1, which belongs to class A serine B-lactamases).
K. pneumoniae
ESKAPE pathogen that's highly pathogenic among immunocompromised individuals - classified as leading HAI; infection can be caused by endogenous or acquired pathogens; leading cause of community-acquired & nosocomial pneumonia; up to 50% mortality rate.
K. pneumoniae
ESKAPE pathogen that's part of HM (ubiquitous, respiratory, & urinary tracts most common); healthcare, environment, & agriculture all ubiquitous.
K. pneumoniae
not all bacteria can be reliably classified thru gram-staining such as?
acid-fast bacteria or gram-variable bacteria
because b-lactam antibiotics mimic D-Ala-D-Ala structure, they bind transpeptidase _____.
active site
structural work revealed that resistance to B-lactams isn't due to antibiotics' poor fit into active site but is due to inefficient formation of ____. ____ formation between methicillin & PBP2 is 1,000 less efficient.
acyl-PBP intermediate
provides long-term protection against re-infection; takes longer than innate response.
adaptive immunity
activation of _____ is much less understood than _____.
adaptive immunity; innate immunity
reduced active form of metronidazole nonspecifically & irreversibly covalently binds to DNA, forming DNA _____; _____ inhibit nucleic acid synthesis, leading to bacterial death.
adducts
majority of mutations are in highly conserved _____.
amino acids
manifested by protein variants that have alternate proteins that have same functions as other antibiotic target proteins but are structurally different; can replace activity of other antibiotic-sensitive proteins in presence of antibiotics. e.g., methicillin-resistant Penicillin Binding Protein (PBP2a) that confers resistance to methicillin.
antibiotic target replacement
type of MOA that involves target modification; replacement/substitution of antibiotic action target.
antibiotic target replacement
kill bacteria or inhibit their growth.
antibiotics
once a symptomatic STD infection develops, it's always treated w/ ____ (if bacterial infection).
antibiotics
spread of antibiotic resistance starts w/ ____ - George gets dose & develops resistance in his gut.
antibiotics
§ Treat a disease § Target invading pathogen § Short-term effect § Increase virulence of diseases by fueling resistance § Pollute environment
antibiotics
this gene encodes for B-lactamases (enzymes that degrade B-lactam antibiotics); seen in penicillin-resistant S. aureus.
blaZ
identification of species-specific compounds is advantageous over _____ antibiotics, because other bacteria won't be affected.
broad-action
type of antibiotic that affects broad range of gram (+) & gram (-); prescribed when causative agent is unknown.
broad-spectrum
in structure of antibiotics, the R group (gets _____ w/ each generation) attached to B-lactam ring.
bulkier
come from bacteria; have sulfur to carbon substitution @ thiazolidine ring; double bond between C2 & C3 of the 5-membered ring; use is reserved for high-risk or severe infections.
carbapenems
carry & release ABR-bacteria from water tanks.
cargo ships
polymyxins poke holes in bacterial _____.
cell membranes
for prevention & control: only use antibiotics when prescribed by a _____, & never demand antibiotics if your _____ says they're not necessary. also, always follow your _____'s advice when using antibiotics.
certified health professional
type of antibiotic target modification that concerns lipopeptide ressistance; common resistance mechnism developed by bacteria against cationic peptides; positively charging cell envelope.
charge alteration
rational design is an approach in which new drugs are discovered based on designing a molecule that's predicted to bind its target based on _____ & shape complementation.
charge; complementation
most commonly reported STD w/ approx. 1.7 million cases reported in 2017.
chlamydia
broad-spectrum bacteriostatic; binds to 50th ribosomal subunit of bacterial ribosomes, & it inhibits peptidyl transferase; small; suppresses bone marrow activity & increases chances of developing aplastic anemia from 1:500k to 1:40k; physicians are advised not to use this antibiotic for infections where alternatives can be used.
chloramphenicol
in 96-well plate of MIC test/dilution method, inoculated bacteria are killed/inhibited in a _____ manner.
concentration-gradient-dependent
type of HGT; most common way by which ABR genes migrate between & among species; requires cell-to-cell interaction.
conjugation
constantly being expressed.
constitutive
_____ ions on the surface are recognized as an essential nutrient & enter the cell; a lethal dose of _____ ions interferes w/ normal cell functions & membrane integrity; _____ ions impede cell respiration/metabolism sometimes causing DNA damage.
copper
B-lactam antibiotics bind transpeptidases much stronger than D-Ala-D-Ala; the binding is _____ & _____, resulting in inhibition of enzyme, cell wall synthesis, & consequently death by cell lysis.
covalent; irreversible
antibiotics are classified as ____ if they meet both WHO criteria 1 & 2.
critically important
DNA synthesis requires nucleoside triphosphate (_____) of each of these bases: dATP, dGTP, dCTP, & dTTP.
dNTP
part of adaptive immunity; special cells called _____ & _____ are recruited to fight microbes & record info about them to create memory of what the invaders look like & how to fight them; useful if another infection by same pathogen occurs but takes time.
B cells & T cells
excretion of most common antibiotics (_____ & _____) generally exceeds 50%.
B-lactams & tetracyclines
a biofilm is a diverse community with complex cell-cell chemical signaling (____); triggers cells to produce & release protective coating that forms a shield around microbial community, protecting it from all outside insults, such as antibiotics, immune response, & so on.
quorum sensing
biofilms continue to divide until stop & turn on their cell-to-cell signaling (______).
quorum sensing
vaccines are not 100% effective, which can create a selection for _____.
resistance
type of MOA that targets antibiotic availability; deletion of a gene (usually a porin).
resistance by absence
type of screening platform for new antibiotics; identification of compounds that target gram-negative bacteria is much more difficult than gram-positive, due to intrinsic barrier that isn't penetrable for most molecules.
rule of penetration
type of screening platform for new antibiotics; measuring penetration of a large set of compounds & ranking them will enable the deduction of rules of penetration.
rule of penetration
-mycin comes from?
streptomyces
competitive inhibitors of dihydropteroate synthase (DHPS); inhibit folic acid synthesis by targeting dihydropteroate synthase enzyme; discovered by Gerhard Domagk in 1932; not true antibiotics, because don't originate from bacteria.
sulfa-drugs
Acinetobacter, Klebsiella, & Pseudomonas are _____.
superbugs
_____ are most common source of biofilm in our bodies.
teeth
alanylation: _____ is a glycol polymer component of gram (+) bacterial cell wall.
teichoic acid
7th step of bacterial translation; when ribosome reaches stop codon, polypeptide is released.
termination
efflux system controlled by ____ consisting of 2 genes: tetA & tetR.
tet operon
codes for a transporter protein that removes tetracycline from cell.
tetA
codes for a repressor protein that binds promoter regions to block own expression of tetR & expression of tetA.
tetR
____ penetrate E. coli biofilms.
tetracyclines
most widely used antibiotic in agriculture?
tetracyline
how are Actinomyces resistant to vancomycin?
they turn on van operon before turning on synthesis of vancomycin; w/o this mechanism, bacteria would kill themselves.
ultimate goal of diagnostics?
to provide patients w/ best care & to provide epidemiological data on disease & resistance
RNA polymerase amino acid substitutions result in high fitness costs as a result of reduced _____; rifampicin resistance cripples bacteria a little bit, but that allows them to remain alive.
transcriptional efficiency
type of HGT; movement of genetic material mediated by phage virus; process begins w/ phage binding to donor cell, & phage injects its own DNA into donor cell, as new viral particle assembled, the donor cell DNA gets packaged & incorporated into new viral particle; viruses then lyse donor cell & infect other cells; not as well understood as other modes of ABR transmission.
transduction
major contributor to evolution of these enzymes is ability of bacteria to _____ amongst strains & species.
transfer genetic material
type of HGT; transfer of naked DNA from outside environment, & this mode of gene migrating was observed in Griffith-Mouse infection experiment; competent cell (recipient cell) takes up donor DNA & incorporates into its own genomic DNA; remaining DNA gets degraded.
transformation
uptake of extracellular DNA from dead cells.
transformation
tetracycline-resistant ribosomal protection protein, tet(O), is a ____.
translational GTPase
5th step of bacterial translation; ribosome moves along mRNA until 2nd tRNA in P site, & the process continues.
translocation
_____ reveals polymyxin-mediated disruption of Klebsiella pneumoniae membrane.
transmission electron microscopy (TEM)
B-lactam-containing compounds bind to & inhibit _____.
transpeptidases
Northwestern University study looked at ABR genes in dust collected from 42 different athletic facilities; high _____ concentration correlated w/ higher presence of ARG; ____ resistance cross-reacts w/ medically important antibiotics; use pure soap & water to wash hands & equipment - no fancy antibacterial agents! stick to soap, alcohol, & bleach.
triclosan
in bacteria, _____ is a drug that specifically inhibits bacterial DHFR but has no effect on human DHFR homolog.
trimethoprim
point mutation/deletion/insertion: dihydrofolate is inhibited by ____; AA substitutions @ active site confer most resistance to ____.
trimethoprim
in _____ in E. coli, the inner membrane AcrB portion connects w/ AcrA, a periplasmic portion, & TolC w/ the outer membrane portion. together, these 3 elements form a channel that allows transport of small molecules from cytoplasmic space into _____.
tripartite transenvelope pumps; extracellular matrix
antibiotics do not discriminate between commensal & pathogen bacteria, t/f?
true
biofilms are common not only in oral cavity but also in sinuses, spinal fluid, eye/ear infections, burn wounds, cystic fibrosis, pulmonary infections, & heart among many other infections; important implications in human health. t/f?
true
over our lifetime, our bodies can accumulate ABR genes that may become problematic as we age/immunocompromised. t/f?
true
penicillin found to be nontoxic, t/f?
true
penicillin strongly inhibitory to many bacteria, but does not inhibit growth of original penicillium used in its preparation, t/f?
true
porins do not require energy in order to transport molecules across membranes, t/f?
true
presence of same ABR genes in gram-positive & gram-negative species that reside in human gut. t/f?
true
prodrugs have less side effects. t/f?
true
type of screening platform: "natural product discovery from microorganisms - the Waksman platform - collapsed due to overmining; the large background of known compounds makes discovery impractical; rapid identification of targets by transcription profiling of extracts will solve problem of the large background, & new sources of secondary metabolites will produce discovery platforms."
utilization of genomics/transcriptomics (rapid de-replication w/ genomics & transcriptomics)
work by activating immune system; do not target the infectious agent but target the immune system.
vaccines
in 2-component regulatory system, this is a ligase that catalyzes ester bond formation between D-alanyl & D-lactate of the lipid to pentapeptide.
vanA
soon after vancomycin's clinical use, new vancomycin-resistant strains of S. aureus during end of 1980-1990's began to appear in healthcare settings; their resistance was conferred by ____ that encodes proteins necessary to swap alanine into lactate in lipid II molecule.
vanA operon
Ala ---> lactate prevents ____ binding.
vancomycin
S. aureus cells able to substitute D-Ala-D-Ala in the dipeptide structure of the pentapeptide of lipid to molecule into a lactate by replacing the peptide bond into an ester bond that links the lactate w/ alanine; while this substitution has no effect on cell wall integrity, it completely prevents _____ from binding to the pentapeptide.
vancomycin
_____ was discovered prior to penicillin but was introduced to market in 1958.
vancomycin
analysis of S. aureus vancomycin-resistant isolates revealed that staph has acquired resistance to _____ thru both plasmid w/ vanA & unstable Enterococci plasmid in S. aureus.
vancomycin
VRSA stands for?
vancomycin-resistant S. aureus
bacteria that are ubiquitously in humans; they are commensal, nonpathogenic bacteria that can colonize our bodies; have high potential to shuffle ABR genes between reservoir & human body.
vectors
cocktail of hundreds to thousands of different peptides, some of which have found their medical application such as painkillers or hypertension medicine.
venom
potently decreases MIC of bedaquiline & clofazimine in M. tuberculosis treatment by 8-16-fold; FDA-approved drug used in treatment of hypertension, but it was recently repurposed as a successful efflux pump inhibitor that lowers MIC of antibiotics; didn't have much success w/ other drugs because of toxicity to host.
verapamil
2 types of resistance gene transfer?
vertical & horizontal
resistant gene passed from parent to progeny; represented by mutation in non-mobile chromosomal DNA passed thru next generation as natural inheritance mechanism. e.g., mutation in 23S ribosomal RNA can generate resistance to erythromycin, streptogramin b, clindamycin.
vertical gene transfer
given that oceans are prone to rapid _____ & ____ transport of water masses & they're a key element to human commerce & recreation, this environment may be an important global reservoir of ABR genes.
vertical; horizontal
is the infection bacterial or viral? new rapid diagnostic tools (provide results in minutes) are being developed that can detect specific _____ DNA/RNA. this info can save lives in a matter of hours.
viral
what kind of data is collected (in terms of priority pathogens) at each of the surveillance sites?
· E. coli · K. pneumoniae · Acinetobacter spp. · S. aureus · S. pneumoniae · Salmonella spp. · Shigella spp. · Neisseria gonorrheae
synthesized from dUMP (deoxyuridine monophosphate); requires enzyme thymidylate synthase & cofactor of methylene tetrahydrofolate; dTMP molecule further reduced by ribonucleotide reductase _____, which is then directly used as a substrate for DNA synthesis; limiting amount of cofactor will dramatically affect cell replication; for this reason, conversion of dihydrofolate back into methylenetetrahydrofolate is essential to keep a constant supply of _____ molecules as building blocks of DNA.
dTTP
in bacteria's natural habitat, loss of porins may also lead to drastically ____ bacterial survival. more favorable mechanisms of resistance include changing porin expression levels.
decreased
bacitracin binds to C55, & it inhibits its _____, which then inhibits its shuffling back over the membrane into cytoplasmic space; leads to lysis.
dephosphorylation
one last recommendation for gonorrhea today?
dual treatment w/ an injection of ceftriaxone & oral dose of azithromycin
release signals from cells to communicate w/ all neighboring cells to alert them that it's crowded: "there's been some sort of exposure to an insult, so let's start to produce a matrix of _____"; sticky coat protects cells in biofilm from outside insults.
exopolysaccharides
plasmid-encoded B-lactamases: _____ are endemic in many hospitals around the world; they're one of the most worrying classes of B-lactamases; source of most dangerous, clinically resistant bacteria.
extended spectrum B-lactamases (ESBL)
no effect on MRSA individually, but their combination is more effective at killing MRSA than last-resort vancomycin): § Garlic § Oxgall (cow bile) § Wine § Leek/onion § Copper salts
eye infection recipe (from Bald's Leechbook (Medicinale Anglicum))
most effective treatment for C. diff infections is ?
fecal transfer
taking fecal matter from healthy individual & transferring into intestine of infected individual; done in patients w/ C. difficile infections.
fecal transfer
both sludge from wastewater & manure are used as _____, carrying antibiotics & ABR onto commercial crops.
fertilizers
_____ are particularly concerning, because they're becoming resistant to nearly all drugs that would be considered for treatment.
gram-negative pathogens
bacteria retain crystal violet dye, because high amount of peptidoglycan, which is responsible for holding the dye.
gram-positive
in 2006, EU bans use of antibiotics as ?
growth promoters
it's believed that life, including bacteria, evolved in ocean & 500 mya, it entered dry land & continued to evolve under constant presence of _____.
low concentration of antibiotics
horizontal gene transfer (conjugation) of vanA operon that encodes components necessary for the substitution; activation of vanA operon occurs in presence of ____.
low vancomycin concentration
if the antibiotics patient was taking selected for resistance in _____ bacteria, he/she will have long/harsh treatment; high medical bills; higher risk for complications; & he/she can spread resistant, pathogenic bacteria around healthcare setting.
pathogenic
reservoirs of antimicrobial resistance can migrate to clinical setting posing threat to humans; concerning when found in _____ bacteria.
pathogenic
bacteria that carry ABR genes & are also directly capable of infecting humans; can be picked up from natural environment & infect humans; can also obtain ABR genes from carriers & vectors leading to multi-drug resistance (MDR).
pathogens
gonorrhea resistance: penicillin was apparently very effective; resistance to penicillin & tetracycline were fueled in 1960s by development of birth control pill & sexual revolution; after 4 decades of use, both drugs lost their efficacy. bacteria picked up plasmid-encoded ____ that codes for PBP2 variant, & penicillin was not able to inhibit its activity. also picked up ____, a ribosome-binding protein that binds to the bacterial ribosome & removes tetracycline from ribosome & prevents further re-binding. also, point mutations in ____ gene that code for 16S ribosomal RNA abrogated tetracycline-binding by target modification.
penA; tet(M); rpsJ
high-throughput screening (HTS): rules of _____ will enable building focused libraries for discovering anti-infectives & will revive the HTS platform.
penetration
antibiotics can be naturally produced antimicrobial agents such as?
penicillin
after gonorrhea developed resistance to sulfa drugs after 1930s, they were replaced by a newly discovered _____ & ____.
penicillin & tetracycline.
enzyme that facilitates hydrolysis of B-lactams rendering them ineffective @ killing bacteria.
penicillinase (B-lactamase)
penicillin antibiotics are prone to degradation by _____, which are enzymes produced by bacteria that degrade b-lactam ring & render the antibiotic ineffective.
penicillinases (B-lactamases)
5 classes B-lactam antibiotics?
penicillins, cephalosporins, carbapenems, monobactams, & clavams
_____ antibiotics aren't same as antimicrobial peptides; antimicrobial peptides are synthesized by ribosomes, & _____ antibiotics are _____ (also no mRNA template).
peptide; non-ribosomal
if you stop brushing your teeth, these biofilms cold get out of control & cause ____; a biofilm-associated inflammatory disease of the gums; can affect entire body by promoting ateriosclerosis, systemic inflammation, bacterial imbalance in gut microbiota.
periodontitis
gram (-) bacteria need efflux pumps that span the inner & outer membranes of the _____.
periplasmic space
to combat biofilm infections: bc matrix somewhat penetrable to small molecules, identification of substances that target _____ is an attractive strategy to treat/prevent biofilm infections.
persister cells
attempts made to understand dosing & administration.
pharmacological period
most dangerous class of lactamases - ones that are encoded on _____ (can easily be transmitted between bacterial cells).
plasmids *light purple = penicillins & 1GC *purple = 2GC, 3GC +/- 4GC *dark purple = carbapenems +/- other B-lactams
mobile genetic elements include _____, _____, & _____ driven by conjugation.
plasmids, transposons, & conjugation
allow molecules into cells (unlike efflux pumps); reduce concentration of antibiotics even before pumps get the chance to pump them out; provide first-line defense against toxic compounds; intrinsic resistance of gram (-) (e.g., P. aeruginosa).
porins
bacteria alter membrane charge thru _____ (addition of amino acid, lysine) of membrane phospholipids.
lysinylation
Fleming was 1st person to identify/work on antimicrobial proteins; discovered _____ that he isolated from tears/sweat
lysozymes
bacteriolysis induced by selected lytic phage or phage cocktails; most promising option - focuses on viruses that specifically attack/lyse bacteria; not easy to use; have to develop a cocktail for each patient's own islet; seems to be relatively safe.
lytic bacteriophage
in the AmpG-AmpR-AmpC pathway, ____ & releases fragments of peptidoglycans known as muropeptides.
lytic transglycosylase (LT)
characterized by macrocyclic lactone connected to sugar moiety via glucosidic bonds; high affinity for 50S ribosomal subunit, where they actually bind to same site as lincosamides; bind to proximal end of peptide exit tunnel, thru which nascent polypeptide chain grows & consequently, inhibits peptidyl transferase from adding additional AA's to growing polypeptide chain. e.g., erythromycin, clarithromycin, & azithromycin.
macrolides
AMR in aqua-/agriculture selected for by _____.
manmade antibiotics
targeting host _____ inhibits bacterial infection.
metabolism
sequencing of whole-community DNA can overcome need for prior knowledge of resistance genes; has been used to detect ABR in diverse environments.
metagenomics
many _____ are found to be essential for bacterial survival; therefore, their sequestration can have an antibacterial effect, or _____ can have direct antibacterial effect. e.g., gallium treatment for P. aeruginosa.
metals
ARB may also be enriched due to other non-antibiotic selective pressures, such as?
metals or biocides
after S. aureus became resistant to penicillin, _____ was introduced to market in late 1950s.
methicillin
after resistance to penicillin, _____ became preferred antibiotic against Staph infection; shortly after its intro, _____-resistant (MRSA) strains began to appear in healthcare setting.
methicillin
narrow spectrum, b-lactam antibiotic discovered in 1960; 1st penicillin-derived antibiotic resistant to cleavage of penicillinases.
methicillin
type of DNA-disrupting antibiotic; functions at level of DNA replication & DNA transcription; synthetic derivative of parasitic drug produced by Streptomyces; when discovered, cured bacterial & parasitic infection; known to induce DNA damage; belongs to large class of drugs called ansamycins (other drugs in this class used for cancer treatment).
metronidazole
using wrong animal infection models in development of S. aureus vaccine: _____ are less sensitive to superantigens compared to humans (i.e., LPS LD in humans ~0.01g ug/kg, in mice > 80,000 ug/kg). this can decrease the toxic effect of the immune response seen in humans; _____ would be a better model, more similar to humans in this regard.
mice; rabbits
-micin comes from?
micromonospora
ABR highly dynamic, & all ABR reservoirs are connected together, allowing _____.
migration of resistance
example of rapid onset of infection by ESKAPE pathogens: cause _____ - the rapid decomposition of tissues (flesh-eating infections); can digest human tissue within hours & kill within 2 days, despite medical attention.
necrotizing fasciitis
A. baumannii is a gram-_____ ESKAPE pathogen.
negative
Enterobacter spp. is a gram-_____ ESKAPE pathogen.
negative
K. pneumoniae is a gram-____ ESKAPE pathogen.
negative
P. aeruginosa is gram-____.
negative
in B-lactamase testing, more specifically modified hodge test (MHT), _____doesn't have any B-lactamase activity, we see that the zone of inhibition is intact because of diffused carbapenem from disk.
negative control strain (#2)
not readily absorbed thru the digestive system & is highly toxic; use is restricted to topical use only, but it can still cause hearing loss even when overapplied as topical medication to a wound.
neomycin
one of the most toxic aminoglycosides.
neomycin
use of vancomycin restricted due to its high _____ (5-43% patients); preferable treatment for S. aureus infections = methicillin; w/ emergence of MRSA, vancomycin use brought back as last-reserve antibiotic despite high toxicity.
nephrotoxicity
newly discovered ribosomal inhibitor; non-ribosomal peptide isolated from Xenorhabdus nematophila bacteria isolated from nematodes; binds specifically to small ribosomal subunit at a completely novel site (compared to other known translational inhibitors).
odilorhabdin
stimuli for efflux pumps to induce expression?
presence of reactive nitrogen & oxygen species; ntimicrobial peptides; antibiotics; antibacterial agents (i.e., triclosan); membrane-damaging biocides
inhibition of uptake becomes priority when dealing w/ infections by intracellular bacterial pathogens; these bacteria need to enter host cells; by inhibiting their cellular uptake, we can attenuate infection. § For typical extracellular pathogens (e.g., ESKAPE pathogens), it's necessary to enhance the ability of phagocytic macrophages to scavenge & engulf these bacteria so they can be killed.
prevent/enhance bacterial uptake
activated by anaerobic bacteria (reduces metronidazole to its active form), leading to formation of DNA adducts; thus, drug only active against anaerobic bacteria (e.g., C. difficile, H. pylori, bacterial-vaginosis-causing bacteria, etc.)
prodrug
_____ have increased activity against strains overexpressing activating enzymes; hence, the specificity of these drugs can be easily validated by targeting enzymes involved in its activation.
prodrugs
type of screening platform; _____ are compounds that get activated once taken up by host; delivered in inactive form & get activated once inside a bacterial cell; activated either by host or bacterial residence.
prodrugs
stimulate immune system to prevent infections.
prophylactic vaccines
~3,000-9,000 different _____ per bacterial cell.
proteins
action very marked on _____ & _____ (gram-positive) group of bacilli; many bacteria quite insensitive (e.g., coli-typhoid group, influenza-bacillus group, & enterococcus).
pyogenic cocci; diphtheria
quantification of hundred of important ARG's & other genes of interest thru parallel assays.
quantitative PCR
antibiotics that bind to & inhibit type II topoisomerases.
quinolones
concerning ABR threats in U.S.?
- vancomycin-resistant S. aureus - erythromycin-resistant group Streptococcus - clindamycin-resistant group B Streptococcus
_____ that produce vancomycin are resistant to these antibiotics; they substitute lactate for alanine as the component of their cell walls.
Actinomyces
____ & ____ have the lowest prevalence of S. aureus.
Canada & Netherlands
most common pathogens in healthcare setting?
Enterobacteriaceae, Pseudomonas aeruginosa, & Acinetobacter
_____, et al. study found that soil bacteria contain resistant cassettes against 5 classes of antibiotics: B-lactams, amphenicols, sulfonamides, tetracyclines, & aminoglycosides.
Forsberg
o 1928 (same year Fleming made observation on antimicrobial property of penicillium), _____ looked at virulence of S. pneumoniae; mouse/encapsulated bacteria experiment.
Frederick Griffith
_____ goal: "to enable standardized, comparable, & validated date on AMR to be collected, analyzed, & shared w/ countries, in order to inform decision-making, drive local, national, & regional action & provide evidence based for action & advocacy."
Global Antimicrobial Resistance Surveillance System (GLASS)
suggested UDP-MurNAc-pentapeptide must be upstream of B-lactam blockage.
Parker & Strominger
suitable microbe on which to test broth as it is hardy, live well in culture, grows rapidly, & is quite sensitive to penicillin.
Staphylococcus
_____ Requirements for Reporting of ABR Infections by Providers, U.S., 2013 & 2016; study was conducted to examine extent to which state health departments report on AMR; all 50 states were examined at 2 different time points (May 2013 & May 2015); in 2015, 44 states required to report at least 1 antibiotic-resistant infection.
State Health Department
severe cutaneous adverse reaction (also observed w/ sulfa antibiotics & penicillins); manifested by rapid epidermal necrosis (loss of skin tissue); can be caused by metronidazole.
Stevens-Johnson Syndrome
penicillin is characterized by _____ - a 4-membered ring containing a nitrogen attached to a beta carbon.
b-lactam rings
most common form of resistance to b-lactam antibiotics is production of _____, which are enzymes that inactivate these antibiotics by breaking b-lactam ring.
b-lactamases
tend to be thick, thin, or branching.
bacilli
gastrointestinal side effects of antibiotics include?
diarrhea, bloating/indigestion, abdominal pain, & loss of appetide
when Griffith injected mice w/ heat-killed, encapsulated mice; none of the mice ____.
died
penicillin belongs to group of _____, demonstrated by observation that the staphylococci are only completely killed after interval of > 4.5 hr even in concentrations 30-40x stronger than necessary to inhibit culture in broth.
slow-acting antiseptic
observed that proper hand-washing can reduce number of deaths of mothers post-child labor.
Ignaz Semmelweis (1940's)
in 23S rRNA mutations of 50S (MLSB), post-translational modification decreases binding affinity by changing/hindering _____.
binding site
many chemical modifications made to improve efficacy of existing antibiotics.
biochemical period
over 2 million cases of STDs in 2017 in U.S. alone. of these, ____ most prevalent followed by gonorrhea & syphilis.
chlamydia
"a structured community of bacterial cells enclosed in a self-produced polymeric matrix & adherent to an inert or living surface." - Pozo & Patel, 2007
biofilms
sewage waste is rich in bacteriophages that are being studied for their specificity to kill various types of bacteria.
phage therapy
_____ (such as dendritic cells, neutrophils, & macrophages) involved in direct clearance of bacteria; scavenge & kill pathogens directly.
phagocytes
to combat biofilm infections: physical ways of disrupting biofilm using _____, radio frequency, electromagnetic radiation, or ____.
electrical current; ultrasound
classes of antibiotics that inhibit bacterial protein synthesis?
- Aminoglycosides - Chloramphenicol - Oxazolidinones - Tetracyclines - Macrolides - Streptogramins
STD & AMR prevention?
- abstinence - monogamous relationships - personal protection (condoms)
one of the consequences of AMR is higher medical expenses. what makes up these costs?
- additional antibiotic prescriptions - prolonged hospitalization - additional diagnostic/lab tests (to determine resistance) - infectious disease specialist (serious infections)
4 distinct building blocks of DNA?
- adenine & guanine (purines) - cytosine & thymine (pyrmidines) *uracil replaces thymine in RNA.
American Heart Association (AHA) recommends... prophylaxis against infective endocarditis (IE) as a reasonable practice before dental procedures that involve manipulation of gingival tissue or periapical region of teeth or perforation of oral mucosa in patients w/ following heart conditions?
- any prosthetic implanted in heart. - previous history of infective endocarditis (IE) - congenital heart disease - cardiac transplants & abnormal valves
one of the consequences of AMR is prolonged hospital stays. what are the consequences of prolonged hospital stays?
- can lead to additional health problems. - time off work = lower pay/job loss.
VISA phenotype is associated w/ genes involved in...?
- cell wall thickening - reduced autolytic activity - cell wall stimuli - global regulators - production of virulence factors - unknown function
min. list of essential functions needed for life first presented by Darwin:
- chemiosmosis - complementary replication of nucleic acid strands - way for informational molecule to catalyze useful chemical rxns.
innovative screening platforms for finding antibiotics?
- combination therapies - culturing the "unculturable" - prodrug design - high-throughput screening - utilization of genomics/transcriptomics - activating silent operons - species-specific compounds - rules of penetration - rational design - virulence factors - scope of search
3 classes of mechanisms of ABR?
- directly targeting the antibiotic - targeting antibiotic availability - target modification
why is the clinical ecosystem the one w/ highest selection pressure?
- due to misuse of manmade antibiotics. - contains human pathogenic bacteria; most of time, these bacteria carry resistance that carry resistance from antibiotic resistance reservoir.
influencing factors believed to contribute to balance of AMR bacteria in naturally occurring reservoirs are?
- exposure of bacteria to a cocktail of antibiotics/toxic molecules simultaneously - leads to possible selection against ABR. - bacteria encounter many anti-resistant mechanisms (e.g., Bacteria #1 are producing B-lactam antibiotics. Bacteria #2 are responding by producing B-lactamases. Bacteria #1, again, responds by producing clavines that sequester function of B-lactamases).
one of the problems w/ genes that code for the secondary metabolites is that often, they're not being expressed for several reasons; what are they?
- expression requires specific donation (e.g., a presence of other bacteria that compete for nutrients) - majority of bacterial operons coding for secondary metabolites are silent & not expressed in vitro.
in _____: gonorrhea resistant to fluoroquinolones steadily takes hold; CDC modifies treatment recommendations throughout much of decade to keep pace.
2000s
in _____: resistance is so widespread, that CDC no longer recommends fluoroquinolones to anyone in the U.S. to treat gonorrhea
2007
_____ countries provided data on all 9 antibiotics.
22
emerging contaminants in wastewater?
pharmaceuticals, personal care products, endocrine-disrupting compounds, surfactants, pesticides, & flame retardants.
in aminoglycosides, amino groups are positively charged at neutral pH, which allows them to interact w/ negatively charged _____.
phosphate backbone
MLSB resistance: post-translational modification (methylation) of the ____ confers broad resistance to 23S-targeting antibiotics; results in cross-resistance to macrolide, lincosamide, & streptogramin B antibiotics.
23S rRNA
gonorrhea resistance: new resistance to azithromycin recently emerged, mediated by mutations in ____ & efflux pumps.
23S ribosomal RNA gene
bacteria that grow in biofilms are ____ more resistant to antibiotics than their planktonic counterparts.
1,000x
many generations of antibiotics have been developed. e.g., penicillins & cephalosporins generations _____ have been developed.
1-4
efflux pumps provide potential targets against antibiotic resistance, they are?
1. Suppress efflux pump expression by targeting either activators/repressors2. Alter antibiotic structure. 3. Disrupt pump assembly. 4. Disrupt AcrZ IMP (AcrB) interaction. 5. Inhibition of IMP (AcrB) using small molecule inhibitors. 6. Block outer membrane protein, OMP (TolC), using small molecules. 7. Disrupt proton motive force w/ agents such as ionophores.
WHO antibiotic classification based on 2 criteria, what are they?
1. describes antibiotics that are the sole/one of the limited available therapies to treat serious bacterial infections. 2. antibiotics targeting bacteria that are transmitted to humans from non-human sources, or bacteria may acquire resistance from non-human sources.
takes _____ years to introduce a single drug from discovery to bring it to market.
10-20 years
antibiotic resistome exceeds _____ genes. bioinformatic analysis of bacterial genomes predicts that there are over _____ antibiotic-resistant genes.
13k
vancomycin-resistant Staph infections still very rare; in U.S., there are only a handful of these cases - ____ reported to be precise. *all strictly limited to hospital settings; however, all carry common predisposition, which includes prior MRSA or enterococcal infection/colonization.
14
in the U.S., children under _____ aren't allowed in newborn baby unit. this is because children are biohazard incubators & can easily transmit disease to babies.
16
since _____ discovery of a single enzyme penicillinase, # of penicillinases discovered over past 5 decades has skyrocketed.
1940
in _____, FDA approved first antibiotics for use in poultry, pork, & beef growth promotion.
1951
target-based antibiotics were being developed in the _____.
1980's
VRSA not common, but they do exist; resistance is thought to originate from glycopeptide-resistant Enterococci thru 2 different genetic events. what are they?
1st possibility: plasmid w/ vanA is conjugated from Enterococcus to S. aureus recipient cell; some Enterococci plasmids are stably expressed in S. aureus; hence, S. aureus capable of maintaining Enterococci plasmid that harbors vancomycin-resistant genes. 2nd possibility: Enterococci plasmid not stable in S. aureus; in this case, Tn1546 transposon capable of removing DNA from donor plasmid & incorporating that into S. aureus-compatible plasmid followed by loss of Enterococcal plasmid.
Canada & Netherlands have the lowest prevalence of S. aureus. why?
2 different factors involved in policy of isolating patients w/ MRSA in hospitals (even if suspected MRSA) & control of prescribed antibiotics within the population (both countries have very low prescription rates of antibiotics).
· CDC estimates AMR causes _____ infections annually causing 23k deaths in U.S. alone.
2 million
one of the 2 strategies that gram (-) bacteria evolved to induce B-lactamases; allows cell to sense outside environment & respond accordingly thru signaling cascade; made of BlrA sensory kinase & a BlrB response regulator. not well understood, & most evidence from its involvement comes from genetic studies in Aeromonas:
2-Component Regulatory System
presence of any extracellular signal such as an antibiotic allows a cell to quickly defend itself by activating production of B-lactamases. this is an example of?
2-component regulatory system (TCRS)
type of enzymatic modification (type of antibiotic inactivation); involves phosphate group addition.
phosphorylation
average protein size?
300 amino acids (~1 kb)
2 large subunits of prokaryotic 70S ribosome?
30S & 50S
GLASS program has set targets that are supposed to be met on annual basis; objective is to reach _____ participation of WHO members.
40%
only _____ of healthcare personnel adhere to hand hygiene.
40%
w/ infectious diseases, time is important (e.g., for a sepsis patient, the survival rate decreases _____ per hour of delay in antibiotic administration); knowing what type of antibiotic needs to be administered to properly target the causative microbe is extremely crucial.
7.6%
protein synthesis facilitated by ____ ribosome in prokaryotes.
70S
Tet(O) is structurally similar to EF-G & can therefore bind to the bacterial _____.
70S ribosome
as of December 2018, _____ countries enrolled in GLASS (a 36% enrollment).
71
does antibiotic prophylaxis really work? UK: no change in infective endocarditis (IE), but _____ reduction in antibiotic prescription, & antibiotic use remained at 2,000 dental prescriptions per month. another follow-up study 5 years after the "no antibiotic recommendation" showed a significant _____ in incidence of IE; however, during this study the antibiotic prescription still remained at 1,300/month.
78.5%; increase
____ of antibiotic-related ER visits are due to allergic reactions.
79%
it takes _____ on average from intro of new antibiotc to clinical resistnance.
8 years
_____ of antibiotics used in U.S. given to animals.
80%
_____ of diseases are transmitted by touch.
80%
protein synthesis facilitated by ____ ribosome in eukaryotes.
80S
"uncultured" microorganisms make up _____ of the total diversity.
99%
ESKAPE pathogen almost exclusively associated w/ hospitals; ~ 12k infections in U.S./year; 64% are multi-drug resistant (MDR).
A. baumannii
ESKAPE pathogen that has plasmid-encoded B-lactam resistance (i.e., imipenem): metallo-B-lactamase (blaIMP) & oxacillinase serine B-lactamases (blaOXA); also has colistin resistance bc complete loss of LPS.
A. baumannii
out of 130 clinical isolates of MDR-bacteria, 6-8% honey exhibited MIC for _____ (including pan-resistant strains) & 12-14% for all other bacterial species tested.
A. baumannii
from metagenomics, we know soil is one of largest reservoirs of ____.
ABR genes
soil is largest reservoir of ____; also, it's one of the largest reservoirs of bacteria.
ABR genes
_____ is difficult even at national level for highly developed countries w/ resources & sufficient funding.
ABR surveillance
most common side effects of antibiotics?
ABR, gastrointestinal, allergic reactions, itchy skin, rashes, photosensitivty, organ damage, tooth discoloration, neurotoxicity, & hearing loss
aminodeoxychorismate then converted by _____ to PABA.
ADC lyase
converts chorismate compound to aminodeoxychorismate.
ADC synthase
ADC synthase & lyase facilitate the synthesis of PABA thru series of reactions facilitated by 2 different enzymes: _____ & _____.
ADC synthase; ADC lyase
2014 WHO global report: "_____ within wide range of infectious agents is a growing public health threat of broad concern to countries & multiple sectors increasingly, governments around world beginning to pay attention to a problem so serious that it threatens achievements of modern medicine; a post-antibiotic era - in which common infections & minor injuries can kill - far from being an apocalyptic fantasy, is instead a very real possibility for 21st century."
AMR
this class of membrane efflux pumps involves transporters hydrolyze ATP on cytoplasmic side of membrane to drive either efflux or influx of small molecules.
ATP-binding cassette (ABC)
_____ is a recently discovered antibiotic that inhibits ADC synthase; therefore, inhibits PABA synthase. result: synthesis of dihydrofolate is inhibited, & bacteria can't make dTTP - cell cycle arrest. recently discovered (2004), so it's still not available commercially.
Abyssomicin C
antibiotic from new species of the _____ - constitute a group of fungi, which might well be called ultra-molds.
Actinomycetes
2-component regulatory system is not well understood, & most evidence from its involvement comes from genetic studies in _____: - overexpression of BlrA increased production of B-lactamase. - BlrA knockout attenuated expression of B-lactamase. - these results suggested that BlrA may be a?
Aeromonas; sensory kinase
one of the 2 strategies that gram (-) bacteria evolved to induce B-lactamases; for the most part, this is conserved but whose variations exist throughout gram (-) species. upon B-lactam antibiotic treatment, muropeptides (fragments of peptidoglycans) are transported into cytoplasm by AmpG transporter.
AmpG-AmpR-AmpC pathways
gram (-) bacteria evolved 2 strategies to induce B-lactamases, what are they?
AmpG-AmpR-AmpC pathways & 2-component regulatory system (TCRS), BlrAB (a histidine kinase 2-component system)
in Bulgecin A, turns out that inhibition of lytic transglycosylase inhibits the generation of muropeptides & decreases production of B-lactamases thru ____, which in turn increases efficacy of B-lactam antibiotics.
AmpGRC system
Mycobacterium fluoroquinolone resistance protein A (MfpA) mimics _____; thus, _____ binds to DNA gyrase (bc, it mimics it) & inhibits its activity.
B-form DNA
Streptomyces makes & secretes _____ into extracellular space that cleaves sugar moiety from oleandomycin, turning it into active form (on outside of cell). oleandomycin gets activated once outside of cell & poses no threat to Streptomyces cells that produced it.
B-glucosidase
since penicillin happens to have ____, it's hydrolyzed by B-lactamases (aka penicillinases).
B-lactam
another type of testing for antibiotic sensitivity is known as _____ also called Modified Hodge Test (MHT); phenotypic test for detection of B-lactamases (carbapenemases); plate contains 4 strains.
B-lactamase testing
production of _____ by gram (-) & (+) bacteria compromises effectiveness of many clinically important antibiotics (of course, these are the B-lactam antibiotics).
B-lactamases
Genes that Forsberg isolated from soil bacteria include?
B-lactamases, efflux pumps, nucleotidyltransferase, resistant variant of DHPS, & acetyltransferase
antibiotic agents that contain a b-lactam ring in molecular structure; includes penicillins, cephalosporins, monobactams, & carbapenems; target bacterial cell walls; work better in gram (+).
B-lactams
allergic reactions, itchy skin, & rashes are side effects caused by which antibiotic?
B-lactams (pencillin)
combination therapies inhibit AMR mechanisms: _____ (tazobactam, sulbactam, avibactam).
B-lactams/clavams
TCRS-controlling B-lactamase Synthesis: ____ is a transmembrane sensor that sits in the membrane, that upon exposure/presence of B-lactams, it auto-cleaves itself, & cleaved fragment becomes a protease that leads to proteolytic cleavage of BlaI (the _____).
BlaR1; transcriptional repressor
TCRS-controlling B-lactamase Synthesis: the protease, ____, cleaves & inactivates BlaI repressor leading to activation of blaZ expression.
BlaR2
Staphylococcus resistance to B-lactams is mediated by blaZ B-lactamase; expression of blaZ is negatively regulated by ____, which is a transcriptional inhibitor that binds to the promoter region of blaZ & prevents activation of blaZ transcription.
BlaI
TCRS-controlling B-lactamase Synthesis: upon exposure to B-lactams, _____ cleaves itself & becomes an active protease.
BlaR1
when _____ infects macrophages, inhibits TCA cycle & shifts cell metabolism into _____, meaning glucose can now ferment into _____ in presence of oxygen; called the Warburg Effect.
Brucella abortis; aerobic glycolysis; lactic acid
compound that selectively binds to & inhibits bacterial lytic transglycosylase (enzyme responsible for clipping & releasing peptidoglycan as muropeptides) - increases efficacy of B-lactam antibiotics.
Bulgecin A
industrial contribution = course of B-lactam antibiotic development; developing new & different antibiotics; _____& _____ studies have opened up phylogenetic relationships of wall variants & B-lactam inhibitors.
Bush & Mobashery's
characteristics of _____: - healthy individuals - previously not exposed to hospital settings - curable w/ right antibiotics - more susceptible to antibiotics - more virulent - this is thought to be the case, because they are able to attack health individuals.
CA-MRSA
the ____ & ____ constantly monitor infection & antibiotics that are being used against them. use best efforts to curb spread of antibiotic resistance, but it's still very difficult to do so, because many countries do not adhere to any guidelines on antibiotic use.
CDC & WHO
unit used to estimate number of viable bacteria under assumption that single bacterium will form a single colony.
CFU (colony forming unit) *hence, 1 bacterium = 1 CFU
currently, _____ is in charge of standardizing diffusion method along w/ other techniques used around the world.
CLSI
newly emerging ESBL called _____ is currently emerging in people w/ no medical conditions, no previous antibiotic exposure, nor any previous contact w/ a healthcare setting. estimated that between 5-10% of population in Southeast Asia & eastern Mediterranean countries are infected w/ bacteria carrying _____.
CTX-M
first clinical use of penicillin done by ______, a med student at St. Mary's Hospital Medical School; obtained culture from Penicillium from Fleming & used to treat hist patients using crude extracts containing penicillin.
Cecil George Paine
worked together on purification of penicillin from Penicillium mold; published work on "penicillin as a chemotherapeutic agent."
Chain & Florey
Frederick Griffith 1928 mouse experiment determined that mice weren't important for this event to occur; transfer of genetic material between live & dead material could be carried out in test tube. 2 decades later, scientists demonstrated that it was _____ that was responsible for transfer of harmless bacteria into virulent bacteria.
DNA
type of point mutation/deletion/insertions that result in a decrease of quinolone binding affinity; confers DNA quinolone resistance
DNA gyrase & topoisomerase IV
quinolones - type II topoisomerase inhibitors w/ ____ being one of the most widely used antibiotics.
Cipro
one of the most widely used antibiotics.
Ciprofloxacin (fluoroquinolone)
recognized as gold standard for medical lab standards; works to improve quality, safety, & efficiency of medical lab testing around the world; formerly known as National Committee for Clinical Laboratory Standards (NCCLS).
Clinical Laboratory Standard Institute (CLSI)
used to see if patient needs medical treatment or to see if infection/abnormality is present; to see if drug would be effective for particular disease; work of _____ helps provide standard for labs to produce best result/decision-making for healthcare/patients.
Clinical Laboratory Standard Institute (CLSI)
enzymes responsible for introduction of negative supercoils into DNA; can relax a positively supercoiled DNA or introduce negative supercoils into a relaxed DNA; heterotetrametric enzymes composed of 2 subunits: GyrA & GyrB.
DNA gyrase (type II topoisomerase)
most common amino acid substitutions are localized to gyrA subunit of ____ & parC of ____; both of these bind quinolones, & point mutations abolished binding affinity.
DNA gyrase; topoisomerase IV
targets of quinolones?
DNA gyrases (type II topoisomerase)
special role of poles - the templates that maintain the diameter of bacterial cell when bacteria are growing/dividing.
Cole, Doyle, Archibald, Koch, Woldringh, & De Pedro
discovered structure of penicillin using x-ray crystallography in 1945; also did work on vitamin B12 & insulin.
Dorothy Crowfoot Hodgkin
non-pathogenic species of _____ are used in industrial production of amino acids, nucleotides, bioconversion of steroids, degradation of hydrocarbons, cheese aging, production of enzymes, etc.
Corynebacterium
not well understood whether these bacteria require cholesterol as nutrient or for a certain step in infection cycle.
Coxiella
B-lactam-containing compounds mimic?
D-Ala-D-Ala
a substrate of bacterial cell wall transpeptidases (penicillin-binding protein, PBP).
D-Ala-D-Ala
amoxicillin is a penicillin derivative that targets bacterial cell wall by mimicking _____ & binds to & inhibits PBP.
D-Ala-D-Ala peptide
in overproduction of peptidoglycan by S. aureus, decreased cross-linking exposes more ____ that bind vancomycin (VM)B-lact. bound vancomycin forms barrier around cell.
D-Ala-D-Ala peptides
dipeptide found in bacteria.
D-Alanyl-D-Alanine
D-cycloserine inhibits this enzyme responsible for ligating the 2 alanine molecules that make D-Ala-D-Ala.
D-alanine-D-ligase (Ddl)
mechanism of target inhibition is similar to b-lactam antibiotics that bind to PBP & irreversibly inhibit PBP function.
DHFR binding
type of antibiotic sensitivity test using diffusion/dilution is called a(n) _____ using a strip is known as Epsilometer test; combines both diffusion & dilution methods; _____ method to assess antibiotic sensitivity.
E-test; quantitative
one of the most well characterized efflux systems is the _____ AcrAB-TolC efflux pump.
E. coli
in India, between 50-80% of _____ & _____ isolates from either blood/urine are resistant to cephalosporins, fluoroquinolones, folate-synthesis inhibitors, & carbapenems; majority of these isolates acquired from community; China has similar problem.
E. coli & Klebsiella
commensal bacterium that colonizes digestive system of warm-blooded animals, including humans (normally non-invasive but can be if found outside GI tract); most common clinical isolate of UTI's, abdominal/pelvic wound infections, & bacteremia; accounts for ~90% of clinical isolates.
E. faecalis
____ are most commonly encountered bacterial species in hospitals in both developing/developed countries.
ESKAPE pathogens
in 1999, _____ issues ban on common human antibiotic use in animals.
EU
antibiotic side effect that occurs when certain drug is exposed to UV radiation to skin, creating phototoxic or photo-allergic byproduct.
photosensitivity
2 years prior to penciillin's commercialization, _____ & _____ (both instrumental in development of penicillin) made important discovery: identified enzyme from bacteria able to destroy penicillin - 1st official indication of bacterial MOA responsible for ABR. explained that it's not necessary to crush organism in bacterial mill in order to obtain enzyme from it; enzyme was secreted into culture fluid.
Edward Abraham & Ernst Chain
injected material from cowpox virus into 8-year-old boy to create smallpox virus vaccine; it was a success; became first vaccine.
Edward Jenner
allows for displacement of bacteria.
physical trauma
ESKAPE pathogen that is also an opportunistic pathogens; causes meningitis, pneumonia, septicemia, wound, UTI, & abdominal cavity; mortality rate can reach ~ 90%.
Enterobacter spp.
ESKAPE pathogen that's resistant to all classes of B-lactamases: Class A: ESBL & carbapenemases Class B: Metallo-B-lactamases Class C: Plasmidic AmpC Class D: oxacillinases
Enterobacter spp.
ESKAPE pathogen that's ubiquitous in healthcare, environment, & agriculture; part of HGM (intestines).
Enterobacter spp.
ESKAPE pathogen part of HGM; ~ 66k infections in U.S./year; 30% are vancomycin-resistant.
Enterococcus faecium
ESKAPE pathogen that emerged in late 1980s & by 2002, over 60% were vancomycin-resistant; VRE: vancomycin-resistant enterococcus (D-Ala-D-Ala to D-Ala-D-Lac); vanHAX genes located on plasmid-residing transposon; expression of PBP5 (low-affinity penicillin-binding protein).
Enterococcus faecium
ESKAPE pathogen; causes UTI; abdominal/pelvic infections; bacteremia; 3rd most frequent cause of nosocomial bloodstream infections (BSI); up to 70% mortality rate (VRE) depending on infection type.
Enterococcus faecium
original discovery of antimicrobial property of penicillium mold by?
Ernest Duchesne (guinea pig experiment - never published discovery)
over 33k deaths directly related to AMR in?
Europe
bacteria floating as single cells in liquid are?
planktonic
wiping out FL citrus trees across state; caused by Asian citrus psyllid Diaphorina citri Kuwayama; poses huge threat to FL economy & future of citrus industry.
FL's Citrus Green Disease
have developed their own immune responses that repel/kill bacteria. example: L-cyclopropylamine
plants
other strains as sensitive as Staphylococcus is to penicillin?
Gonococci, meningococci, & some gram-negative cocci found in nasal catarrhal conditions
soil bacteria: in Jordan, people used to rub red soil to treat infected skin & diaper rashes. Jordan's red soil is inhabited by bacteria that have strong antimicrobial activity against _____ & _____.
S. aureus & Micrococcus luteus
subnuit of DNA gyrase that mediates enzyme-catalyzed DNA breakage-reunion.
GyrA
DNA gyrase made of ____ & ____.
GyrA & GyrB
most common amino acid substitutions are localized to ___ & ___, subunits that bind quinolones & are responsible for the DNA breakage-reunion.
GyrA & ParC
subnuit of DNA gyrase; ATPase activity & facilitates strand passing.
GyrB
a bacterium that causes lower respiratory infection, & ear/sinus infections.
H. influenzae (also formerly known as B. influenzae)
_____ infections are more resistant to antibiotics; found in a surveillance study that compared 201 different isolates of S. aureus.
HA-MRSA
characteristics of _____: - attacks immunocompromised - known exposure to hospital settings - difficult to cure - more resistant to antibiotics - less virulent - targets immunocompromised individuals in the hospital
HA-MRSA
very high levels of resistance have been observed in bacteria that cause common _____ across all WHO regions.
HAI & CAI
gonorrhea can acquire resistance thru ____, & resistance doesn't seem to have any fitness cost, except for fluoroquinolone's resistance mediated by point mutations in gyrases & topoisomerases.
HGT
gram-positive/gram-negative concept developed by _____ based on structural differences in cell walls of 2 types of bacteria.
Hans Christian Gram
_____ Study: ocean water samples were collected & analyzed for presence of genes that confer resistant to 4 antibiotics: ampicillin, nitrofurantoin, ampicillin, & sulfa drugs; found between 15-32% of all ABR genes came from non-marine organisms that were most likely a source of contamination from land.
Hatosy & Martiny
using ancient medicines isn't such a bad idea; _____ recommended to drink tea brewed from a Willow Tree bark as a potent _____.
Hippocrates; fever reducer
critical analysis of murein composition; ound existence of anhydride structure at end of chains; lead to important model of how bacterial wall grows.
Holtje & Schwarz
____ are the most common transmissible infections (i.e., Hepatitis B virus affects more than 250 million people w/ about 1 million deaths per year).
STDs
population of 1.34 billion; 55 registered surveillance sites; established National Reference Lab & National Coordinating Center; reporting to GLASS from 21 surveillance sites; has reported thousands of samples demonstrating major issue in ABR.
India
more calls to action against ESKAPE pathogens have been proposed by organizations such as _____.
Infectious Diseases Society of America (IDSA)
Clinical Laboratory Standard Institute (CLSI) partners w/ labs across globe & provide lab mentors to improve diagnosis of diseases like malaria, HIV, tuberculosis, etc.; global reach & influence s evidenced by partnerships w/ _____ & _____.
International Organization for Standardization (ISO) & World Health Organization (WHO)
- "educated guess." - non-specific antibiotic prescription. - high potential for failure & development of resistance.
semiprimal diagnostics
2-minute region & PBP's; looked for mutants of E. coli that grew only as filaments, & there were a dozen types of these fts mutants; mutations involved genes that regarded the cell division process & wall growth.
Jacob, Hinda, & Spratt
extended spectrum B-lactamases (ESBL) were initially isolated in 1980's from _____ species; isolation took place in Germany, & soon after initial identification of these strains in Germany, they started to appear in hospitals around Europe.
Klebsiella
bacteria w/ sequestration mechanisms include...
Klebsiella pneumonia, Streptococcus pneumoniae, or Pseudomonas aeruginosa.
safe enlargement; determined that in order for a bacterial cell to safely exist/grow in an aqueous environment, it must... - have a covalently linked, completely surrounding fabric (sacculus). - be able to enlarge he sacculus by addition of units. - break bonds only after new covalent attachments have been made.
Koch, Higgins, & Doyle
immune response compound synthesized by an amanita mushroom that kills/repels bacteria. compounds targets _____, an enzyme required for leucine synthesis.
L-cyclopropylamine; isopropylmalate synthase
number of additional small molecules that target ____, ____, ____, & ____ were identified to increase efficacy of B-lactam antibiotics by inhibiting expression of B-lactamases.
LT, NagZ, AmpG, & AmpR *some of these mimic structures of B-lactams, while others are non-B-lactams.
____ is one of the most common bacteria associated w/ cooling towers that just sporadically infect & kill exposed individuals, especially the elderly.
Legionella pneumophila
criterion determines whether or not a specific molecule will penetrate cell membrane.
Lipinski's "Rule of 5" Guidelines
_____ is concentration of antibiotic that is marked on image w/ star (completely killed/inhibited bacterial growth).
MIC
as concentration of drug increases, the survivability of bacteria decreases until it hits a certain concentration, where growth is completely inhibited/bacteria completely killed. this point is the ____.
MIC
1-2% of the population are _____ carriers; have no obvious signs of infection.
MRSA
S. aureus mutant that has an additional PBP (i.e., PBP 2, which binds poorly to b-lactams but still can function in synthesis of peptidoglycan).
MRSA
_____ is leading cause of HAI's; claims over 10k people each year in U.S. alone; these infections are almost exclusively associated w/ healthcare setting.
MRSA
in 2011, CDC estimated that invasive _____ infected over 80k people & led to over 11k deaths. invasive _____ reporting requirement: only required in 6 states.
MRSA
most common HA-acquired infection in the U.S.: _____.
MRSA
skin & soft tissue accounted for over 80% of all different infection sites of ____, meaning these infections are easily preventable.
MRSA
this drug-resistant bacterium was found outside turkey/pig farms, indicating bacteria can spread thru air & spread resistance outside of contaminated area.
MRSA
_____ & _____ were as sensitive to antibacterial activity of honey as MSSA & VSE.
MRSA & VRE
to conserve energy, S. aureus bacteria turned the expression of PBP to off & only turn it on in presence of B-lactam antibiotics. B-lactams activate ____ (transmembrane sensory kinase) that rapidly induces expression of mecA-mecR1-mecl-medR2 operon.
MecR1
in S. aureus, after expression of mecA-mecR1-mecl-medR2 operon, anti-repressor ____ activity promotes inactivation of MecI inhibitor by its proteolytic cleavage. in absence of B-lactams, MecR1 not activated, MecI dimers inhibit mecA promoter, & residual MecR1 remain at cell membrane.
MecR2
Bald's Leechbook (_____) - 9th century; had eye infection recipe.
Medicinale Anglicum
type of carbapenem; reaches PBP's of cytoplasmic membrane, & it binds to them, interfering w/ ability to create/modify peptidoglycan layer; has high affinity for PBP's 2 &3 - believed to be associated w/ high antipseudomonal activity; not as easily degraded by b-lactamases in periplasmic space of gram (-) as are other antibiotics (stabilized by 6-alpha-hydroxyethyl side chain).
Meropenem (against P. aeruginosa)
bacteria can produce enzymes to enzymatically inactivate antibiotics (other than B-lactams), t/f?
true
_____ was only state required to report HA-MRSA cases; very few required to report all other notable infections noted previously in course.
Missouri
biofilms are ubiquitous, t/f?
true
method of identifying bacterial isolates by directly measuring DNA sequence variation in housekeeping gene (e.g., used on E. faecalis ST16).
MultiLocus Sequence Typing (MLST)
an enzyme that catalyzes addition of enolpyruvate to UDP-N-acetylglucosamine (one of the first steps in peptidoglycan precursor biosynthesis step).
MurA
murein wall; found wall polymer in bacteria (peptidoglycan/murein); found uridine derivatives that were key intermediates in biosynthesis.
Salton, Park, & Strominger
due to impermeable cell envelope, _____ is resistant to receiving genetic material thru HGT mechanisms. thus, the resistance of these bacteria almost exclusively comes from spontaneous mutation inherited thru ____.
Mycobacterium tuberculosis; vertical gene transfer
bacterial cell wall composed of 2 different sugar molecules?
N-acetylglucosamine (NAG) & N-acetylmuramic acid (NAM)
when attached to a pentapeptide, this molecule is called lipid I.
N-acetylmuramic acid
Klebsiella-acquired plasmid-encoded genes code for enzymes that have the capacity of destroying carbapenem antibiotics. e.g., _____?
NDM-1
in AmpG-AmpR-AmpC pathways in cytoplasm, _____ removes NAG (N-acetylglucosamine monosaccharide) sugar group & remaining (N-acetylmuramic acid) NAM-oligopeptide interacts w/ ampR (a transcriptional regulator) located upstream of ampC (B-lactamase gene). consequently, B-lactamases are secreted from this cell, & they degrade any B-lactam antibiotics even before they get a chance to pass thru outer membrane.
NagZ enzyme
_____ was already available as first clinical quinolone for UTI's.
Nalidixic Acid
establishes & oversees the national surveillance program, gathers national AMR data & communicates w/ GLASS.
National Coordinating Center
type of quinolone withdrawn from market due to lack of efficacy in humans; isolated from Actinobacteria streptomyces in 1950's; bacterial gyrase (GyrB) inhibitor.
Novobiocin -
____ capable of penetrating biofilms; once inside of biofilm, virus replicates & disrupts biofilm matrix; then, ____ are able to penetrate & kill exposed cells that were not killed by virus.
OMKO1 Phage; antibiotics
important precursor of dihydrofolate synthesis in bacteria.
P-aminobenzoate (PABA)
ESKAPE pathogen that causes pneumonia, endocarditis, osteomyelitis, UTI, GI infections, meningitis, septicemia, ear (swimmer's ear), & eye (most common infection associated w/ contact lenses); associated w/ immunocompromised individuals, (i.e., burn victims & cystic fibrosis patients); 30% mortality rate.
P. aeruginosa
ESKAPE pathogen that has B-lactamases such as metallo-B-lactamases (blaIMP) & B-lactamases (KPC, VIM, ESBL); also resistant by change in porins & overexpression of efflux pumps.
P. aeruginosa
ESKAPE pathogen that's ubiquitous in healthcare, environment, & agriculture; part of HGM (intestines); ~ 51k infections in U.S./year; 13% are MDR.
P. aeruginosa
_____ requires proper iron homeostasis for growth/replication.
P. aeruginosa
membrane-bound protein that covalently binds penicillin; most bacteria have small number of different kinds numbered from _____ 1 (largest) upward.
PBP
to catalyze cross-linking reaction in well wall synthesis, _____ binds to D-Ala-D-Ala molecule located at stem termini of each peptidoglycan side chain on both gram-positive & gram-negative bacteria.
PBP
fluoroquinolones bind to _____ (breakage-reunion subunit) of DNA topoisomerase IV, which is similar to GyrA subunit of gyrases.
ParC
country of _____ that has population of 38.17 million; registered w/ 70 surveillance sites; established National Reference Lab & National Coordinating Center; has reported data to GLASS; monitoring 8 different bacterial species of high priority: _____ spp. in blood samples of unknown origin was most reported; extent of resistance: _____ isolates from blood were resistant to cephalosporins, ampicillin, & fluoroquinolone but showed sensitivity to colistin & carbapenems. · Data still confusing.
Poland; Acinetobacter; E. coli
_____ has number of recommendations to control infections & use of antibiotics by focusing on key areas that include federal support, implementation strategies, science-based research, workforce, & education & competencies.
Presidential Advisory Council on Combating ABR-bacteria (PACCARB)
in September 2018, the _____ issued document on key strategies to enhance infection prevention & antibiotic stewardship in humans & animals.
Presidential Advisory Council on Combating ABR-bacteria (PACCARB)
Domagk discovered _____ - molecule that was the first commercial antimicrobial; metabolized by intestinal enzymes into active form sulfonamide.
Protodrug Prontosil
_____ is a live, attenuated Brucella abortis vaccine that's capable of activating immune system & mount protective responses but not virulent to cause disease in healthy cows/individuals.
RB51
type of point mutation/deletion/insertions that takes place on RNA polymerase.
RNA polymerase (rifampicin resistance)
ESKAPE pathogen; in Thailand, over 60% of ____ isolates were resistant to methicillin; MRSA: methicillin-resistance _____; mecA (PBP2a) - highly mobile gene that encodes a variant of penicillin-binding protein w/ low affinity for B-lactam antibiotics; VRSA: vancomycin-resistant _____ (D-Ala-D-Ala to D-Ala-D-Lac); vanHAX genes located on a plasmid-residing transposon; vancomycin resistance is mediated by vanA operon in same way as we've seen w/ VRE; presence of vanA operon in both Staph & VRE provides.
S. aureus
there's no vaccine for _____; all staph vaccine trials have failed; most challenging vaccine to be developed.
S. aureus
ESKAPE pathogen that causes skin infections (e.g., impetigo); wound infections; osteomyelitis; pneumonia; bacteremia; & food poisoning; it's the most common HAI; 20-50% mortality rate (sepsis).
S. aureus
ESKAPE pathogen that's part of HM (skin, hair, nose, throat); 30% of population is colonized; healthcare (ubiquitous); environment (ubiquitous); agriculture (ubiquitous); ~ 81k MRSA infections in U.S./year.
S. aureus
vaccine issues associated w/ _____: numerous virulence mechanisms; therefore, targeting one virulent factor will not protect against other factors. all vaccine studies targeted cell surface components, & while these would seem most logical targets, all failed to develop functional response. using wrong animal infection models.
S. aureus
wall synthesis & cellular size control; made suitable mutant & obtained radioactive precursor, so that cells could be suitably labeled & studied by autoradiography under electron microscope.
Schwarz, et. al & Nanninga, et. al
_____ pioneered screening of antibiotics that are made by other bacterial species, mainly Actinomyces.
Selman Waksman
defined antibiotic as "a microbial product that kills/inhibits growth of other microbes," 1942. known as father of all antibiotics; discovered over 15, including streptomycin. saved more lives (millions) than any other scientist.
Selman Waksman
variation of Kirby-Bauer disk diffusion. type of antibiotic sensitivity test w/ plate divided into 3 regions. 2 outside regions are controlled strains w/ known antibiotic sensitivity, & middle section is seeded w/ test bacteria; results compared to control strain.
Stokes Method
variation of Kirby-Bauer disk diffusion; in Kirby-Bauer method, bacterial antibiotic resistance is unknown; in this method called _____, unknown bacteria are compared to known antibiotic-sensitivity samples on same plate.
Stokes method
binds to peptidyl transferase catalytic center on 50S ribosomal subunit; result: tRNA cannot bind to A nor P sites, which leads to arrest of peptide bond formation & cessation of polypeptide elongation; binding leads to conformational changes in the ribosome that enhance binding of Streptogramin B.
Streptogramin A
binds to 23S rRNA within 50S ribosomal exit tunnel, inhibiting growth of the nascent protein, leading to release of unfinished polypeptide fragments.
Streptogramin B
biofilms could be single homogeneous population or heterogeneous population of bacteria, t/f?
true
group from ____ demonstrated for first time that active export of antibiotics is responsible for tetracycline resistance. group demonstrated that active tetracycline transport pumps tetracycline into cells. result suggested that tetracycline resistance is mediated by ____ of antibiotic outside of cell.
Stuart Levy Lab; active transport
how do ABR travel thru air?
aerosol/fluid droplets & solid particles (e.g., Coxiella burnetii caused Q-fever in Netherlands, due to dissemination by wind from nearby goat farms)
isolated from "unculturable" soil bacteria; non-ribosomal peptide made of unusual amino acids; made by gram-negative that's effective in killing gram-positive; thought (not exactly known) to bind to a highly conserved part of lipid II & lipid III (both precursors of cell wall teichoic acid).
Teixobactin
actual immune response to influenza (characterized by activation of _____ & _____ cytokines): these responses aren't fully developed as small child or are not working properly in elderly.
Th1 & Th2
function of murein sacculus; determined that murein (peptidoglycan) polymer was the surrounding layer that gave strength & structure to the bacterial cell & was the unique enclosing fabric; believed that this structure was what led to the development of the domain Bacteria.
Weidel & Pelzer
_____ received Nobel Prize Medicine in 2015 for her discovery of artemisinin.
Youyou Tu
both ampicillin & amoxicillin can kill both gram (-) & gram (+) bacteria, making them ____.
broad-spectrum antibiotics
______ sterically protect axes of B-lactamases to the B-lactam ring; form shield of b-lactam ring, decreasing ability of B-lactamase to inactivate specific antibiotic.
bulky side groups
murein wall must have developed _____ development of much of the cell physiology that's common to all cells, & creation of bacterial wall was an important contributor to development of diversity on planet.
after
a cook for a wealthy family that suddenly developed typhoid fever; investigation found that _____ is a healthy carrier of S. typhi; 7 of the families she worked for contracted typhoid fever.
Typhoid Mary
population of 324.46 million; 3,949 surveillance sites; selected its National Reference Lab & National Coordinating Center; we have not reported data since 2018; looking at previous data but limited to CA-acquired cases of gonorrhea.
U.S.
treatment of bacteria w/ sublethal concentrations of penicillin led to accumulation of a molecule _____.
UDP-N-acetylmuramyl-pentapeptide (UDP-MurNAc-pentapeptide).
recent studies in _____ identified histidine kinase sensor to function directly as B-lactam receptor that translates signal to a response regulator that controls expression of B-lactamase.
Vibrio parahaemolyticus
cross-contamination within _____ also exposes us to ABR bacteria not only thru farm animals but also thru crops.
agriculture
the low cost of tetracycline & their excessive use, especially in _____, lead to rapid development of resistance.
agriculture
_____ has initiated the Global AMR Surveillance System.; early implementation stage 2016-2019.; majority of countries are still not registered & many don't report (funding & resources are major limitation).
WHO
for prevention & control: prepare food hygienically, following the _____ (keep clean, separate raw & cooked, cook thoroughly, keep food at safe temperatures, & use safe water) & choose foods that have been produced w/o use of _____ for growth promotion or disease prevention in healthy animals.
WHO 5 Keys to Safer Food; antibiotics
classifies antibiotics according to importance in treatment of bacterial infections.
WHO antibiotic classification
culturing the "unculturable" combined w/ rapid re-replication is likely to lead to revival of _____.
Waksman screening platform
a phenomenon that's the hallmark of cancer cells.
Warburg Effect
ABR easily travels thru environment by?
air, soil, & water
4 years later (only 2 years after penicillin had been on market) in 1944... _____ was able to extract penicillinase from clinical isolates of penicillin-resistant bacterial strains. during a study of several hundred strains, staph isolates from patients, a few were found which were completely resistant to lytic action of penicillin.
William Kirby
D-cycloserine inhibits this enzyme responsible for racemization of L-alanine into D-alanine; switches chirality of alanine from L to D handedness.
alanine racemase (Alr)
2 steps of D-Ala-D-Ala synthesis that cycloserine inhibits?
alanine racemase (Alr) & D-alanine-D-ligase (DdI)
result of cycloserine = lipid II molecule is missing 2 terminal _____, which leads to disruption of bacterial cell wall & consequent lysis.
alanines
2nd step of bacterial translation; on assembled ribosome, tRNA carrying first AA, formylmethionine is paired w/ start codon on mRNA @ P site (place on ribosome where first tRNA sits is called P site); AUG start codon on mRNA is read by UAC triplet anticodon on formylmethionyl tRNA; tRNA carrying 2nd AA approaches A site on ribosome & recognizes 2nd codon on mRNA molecule; in A site, next to P site, 2nd codon of mRNA pairs w/ tRNA carrying AA.
accomodation
mechanism that Forsberg isolated from soil bacteria; gene that encodes for an enzyme that adds an acyl group to inactivate antibiotics; fall in same mechanistic category as nucleotidyltransferase aadB.
acetyltransferase
intrinsic resistance is not as dangerous as _____ (usually cause of contamination from farm animals).
acquired
biofilms form complex spectral communities, & can therefore, develop antibiotic resistance thru number of mechanisms including physical barriers, antibiotic degradation, presence of persister cells, biofilm-specific efflux pumps, activation of stress responses, or changing the microenvironment of the biofilm. antibiotic degradation, efflux pumps, & activation of stress responses are involved in ____.
acquired antibiotic resistance
plasmid-encoded B-lactamases are responsible for _____.
acquired resistance
process used to remove nutrients from wastewater; microbes oxidize carbonaceous biological matter & nitrogenous matter & clump together to form _____; part of this is recycled back to process, but part of it is removed as excess; excess goes thru anaerobic digestion & composting before it's use, for example, in a landfill.
activated sludge
_____ is a type of screening platform that deals w/ secondary metabolites that aren't being expressed; while there's no effective way of turning these genes on, one approach being developed is to clone entire operons into different bacteria under inducible promoters. can provide important advancements in the hunt for novel antibiotics..
activation of silent operons
type of enzymatic modification (type of antibiotic inactivation); involves addition of acyl (RCO-) group.
acylation
either an _____ or _____ between 2 drugs can drastically enhance the efficacy of antimicrobial therapies. example: screened for molecules that target both the host & the invading bacteria at same time. these dual targeting compounds are much more potent than separately targeting bacteria or separately targeting the host.
additive; synergistic effect
vaccines also have other additives including _____ - molecules that boost immune system. antibiotics, stabilizers, & preservatives that prevent vaccine from contamination & increase their stability & trace components that remain after vaccine manufacturing process.
adjuvants
study found close correlation between ABR genes in river water, droppings of _____ who lived near that water, & soil in park where _____ were living; suggests _____ can spread bacteria carrying ABR genes between environments thru their feces.
birds
where did ocean AMR come from in terms of non-marine origin?
birds, cargo ships, aqua-/agriculture, & wastewater
the B-lactamase genes that Forsberg isolated from soil bacteria were encoded by? *found in Acinetobacter, Klebsiella, Pseudomonas, Salmonella, & Proteus
blaP1
S. aureus began to confer resistance to penicillin mainly by expressing ____ gene, which is a 2-component regulatory system.
blaZ
TCRS-controlling B-lactamase synthesis: Staphylococcus resistance to B-lactams is mediated by _____.
blaZ B-lactamase
type of peptide antibiotic; isolated from strain of bacillus in tibial fracture wound of 7 year-old girl; known as OTC ointment antibiotic usually applied to minor skin infections.
bacitracin
"regular toothbrushing & flossing pose a greater risk in relation to both infective endocarditis & prosthetic joint infection than episodical dental treatment; toothbrushing, flossing, pulsating water irrigators, & interdental wood sticks can all produce _____."
bacteremia
it is thought that ____ was the first of the 3 domains to have split off the main trunk.
bacteria
majority of discovered antibiotics come from ____; hence, these bacteria carry resistant mechanisms that provide them w/ immunity against their very own antibiotics.
bacteria
MfpA-binding protects DNA gyrases from quinolone-binding, whenever they're not bound to _____.
bacterial DNA
cephalosporins & glycopeptides (e.g., vancomycin) target _____.
bacterial cell wall
electrostatic interaction between lipopeptides & bacterial membranes make these lipopeptides effective at targeting & disrupting the ____.
bacterial cell wall
what is conjugation?
bacterial mating
alone, trimethoprim & sulfamethoxazole are bacteriostatic, but when combined, they become _____.
bactericidal
_____ are not antibiotics, but they do provide good alternative.
bacteriophages
there's a fine _____ of AMR bacteria in naturally occurring reservoirs; believed that this _____ has remained for thousands of years.
balance
if bacteria require resistance mechanisms to survive antibiotics they produce, then that means antibiotics resistance must have come _____ antibiotics. such mechanisms were most likely efflux pumps that were involved in pumping other molecules out of cells.
before
why aren't tetracyclines recommended for chidlren?
can cause teeth discoloration
uncontrollable cell division; may be controlled using chemotherapeutic agents. in some instances, _____ develops resistance to these drugs making it more difficult to treat.
cancer
type of antibiotics that cause liver damage?
carbapenems, rifampin, isoniazid, & tetracyclines
since _____ are last-reserve antibiotics for many bacterial infections, especially for drug resistant severe infections, the most dangerous B-lactamases are _____ including KPC1, VIM, IMP, NDM1, & OXA-48 variants. both KPC1 & NDM1 leave very little antibiotic options for patients infected w/ bacteria that carry these plasmid-encoded _____.
carbapenems; carbapenemases; carbapenemases
bacteria that carry antibiotic resistance genes but are not pathogenic themselves; can't even infect/colonize humans.
carriers
mobility of ABR genes between their natural reservoirs/hosts, including human/farm animals, mediated by?
carriers, vectors, & pathogens themselves
currently, _____, 3rd-generation cephalosporin & ____ (a macrolide antibiotics that binds to 50S ribosomal subunit to inhibit protein synthesis) are only recommended treatment options.
ceftriaxone; azithromycin
issues w/ today's treatment of gonorrhea: abroad infections resistant to _____ have been detected in several countries & within U.S. (while not common), resistance to ____ has been found. *this dual treatment won't last forever, so we must keep drug-resistant gonorrhea as a leading priority.
ceftriaxone; azithromycin
2 common forms of S. aureus resistance to vancomycin have been identified: o one changes _____ structure. o other replaces the _____.
cell wall; PBP
explanation of the flow of genetic information within a biological system. - replication of DNA - transcription of DNA into RNA - translation of RNA into proteins
central dogma of molecular biology
in 2011, CDC classified Neisseria gonorrheae as urgent threat underlining that ceftriaxone + either azithromycin/doxycycline are the first-line treatment options for gonorrhea, & that emergence of _____ would greatly limit treatment options & could triple gonorrhea control efforts.
cephalosporin resistance
come from mold; discovered by Giuseppe Brotzu; both penicillins & cephalosporins target same class of PBP's; less susceptible to penicillinases; 6-membered ring attached to B-lactam ring.
cephalosporins
only one class of antibiotics remains to treat gonorrheal infection - _____.
cephalosporins
today: quinolones replaced by ____, to which gonorrhea began to develop resistance in just under a decade by acquisition of plasmid-encoded extended-spectrum carbapenemases.
cephalosporins
why are flu vaccines constantly re-developed?
certain influenza therapeutics or prophylactics such as vaccines quickly lose effectiveness as the virus mutates.
from Streptomyces, but much cheaper to synthesize in vitro because of its structure; 1st antibiotic synthesized in test tube; broad-spectrum bacteriostatic, because it functions by inhibiting protein synthesis; inhibits replication but does not kill cells - bacteriostatic; small size allows its diffusion to body areas normally inaccessible by antibiotics; used in treatment of bacterial meningitis; serious side effects; binds to 23S ribosomal RNA of 50S ribosomal subunit - leads to inhibition of peptidyl transferase.
chloramphenicol
these antibiotics target peptidyl-transfer center (PTC) of 50S ribosomal subunit. *inhibited by bacterial ATP-binding cassette F (ABC-F) ribosomal protection protein.
chloramphenicol, streptogramin A, & lincosamides
antibiotics that target translation at the 50S ribosomal subunit; broad-spectrum antibiotic that typically stops bacterial growth by stopping the production of proteins; inhibits replication but does not kill cells - bacteriostatic; binds to 23S ribosomal RNA of 50S ribosomal subunit - leads to inhibition of peptidyl transferase.
chloramphenicols
_____ can act to concentrate various plasmids, insertion sequences, & integrons involved in HGT of ARG's.
chlorination
_____ & _____ have been associated w/ increased proportions of ABR bacteria ARG's.
chlorine; chloramines
resistance to polymyxins is attributed to _____ & therefore, doesn't spread across bacteria.
chromosomal mutation
untreated STDs like chlamydia & gonorrhea put women at increased risk of PID (can result in ____, ____, & ____).
chronic pelvic pain, infertility, & life-threatening ectopic pregnancy
K. pneumoniae (ESKAPE pathogen) has metallo B-lactamase (New Delhi Metallo-B-lactamase-1, NDM-1, which belongs to _____).
class B B-lactamases
_____ are metalloenzymes that require divalent zinc ions for substrate hydrolysis.
class b lactamases
come from bacteria; weakest of all 5 - more responsible for not killing bacteria but for combating ABR; mimic b-lactam antibiotics & saturate b-lactamases by tricking them into being antibiotics; used to enhance penicillin's efficacy against bacteria that produce penicillinases (e.g., B. coli & B. influenzae); combined w/ clavulanic acid, often use Augmentin - commonly prescribed amoxicillin used against bacteria such as H. influenzae also formerly known as B. influenzae.
clavams
these inhibitors are currently used as drugs in combination w/ B-lactam antibiotics to treat infections by bacteria producing B-lactamases, such as ____.
clavams
_____ inhibits b-lactamases, & amoxicillin is able to inhibit peptidoglycan crosslinking.
clavulanic acid
______ is a B-lactam that doesn't possess any antibiotic property itself; however, it does bind to & inhibit B-lactamases preventing their destruction of other B-lactam antibiotics.
clavulanic acid
when the body metabolizes mupirocin, the drug is?
cleaved into inactive monic acid & the CA.
_____ settings were rapidly enriched w/ ABR-bacteria within much shorter period of time.
clinical
strong evidence showing ABR in human pathogenic, ____ strains came from these natural reservoirs (i.e., soil) of ABR genes.
clinical
all 3 microbial ecosystems contribute to selection for antimicrobial resistance, although humans have enhanced mainly the selective pressure in the ____ & ____ ecosystems. also saw some contribution to enhancing selective pressure of the environmental ecosystems.
clinical & non-clinical
highest selection pressure; represents all clinical settings like hospitals.
clinical ecosystem
where relative concentration of antimicrobial agents is high, leading to very high selective pressure; contributes the most to the development of antibiotic resistance.
clinical ecosystem
when the concentration of antibiotic needed to kill a certain microbe is not achievable in human body, because the concentration would be too toxic.
clinical resistance
if no effective antibiotics around for an infection, the resistance also becomes unnecessary; in general, instead of killing each other, bacteria ____.
coexist
introduction of discovery platforms will increase the probability of finding good lead compounds, which will enable the development of _____ based on 2 compounds hitting 2 different targets. screening platform for compounds that enhance effectiveness of current antibiotics.
combination therapies
resistance rapidly develops against compounds hitting a single target, which automatically eliminates vast majority of targets. solution is this type of screening platform called ____.
combination therapies
if patient develops resistance in ____, nonpathogenic bacteria, he/she will be unaware of the resistance in his body. if patient socializes, he/she spreads resistance thru ____ bacteria.
commensal; vector
a _____ is an infection acquired from a communal setting, such as a gym, swimming pool, subway, etc.
community-acquired infection
most infections occur as?
community-acquired infections
CA-MRSA stands for _____ MRSA.
community-acquired/associated
used to control invasive/disease-carrying pests. e.g., to reduce malaria, population of mosquitoes is controlled by _____.
pesticides
3 types of antibiotic sensitivity tests?
diffusion method, dilution method, & diffusion/dilution
both methotrexate & trimethoprim mimic?
dihydrofolate
positive charge of polymyxin interacts w/ negatively charged LPS chains - specifically ____ portion @ outer membrane of gram (-) bacteria; polymyxins disrupt outer membrane & allow their access into periplasmic space & into inner membrane.
lipid A
effective against gram (+) bacteria; including MRSA & VRE bacteria; oligomerizes inside bacterial membrane, affecting membrane curvature; curvature leads to disruption in membrane integrity.
daptomycin
lysinylation: _____ (cationic antimicrobial peptide) has an overall positive charge; in a normal cell, that positive charge is attracted by negatively charged membrane.
daptomycin
little progress in discovery of new antibiotics recently; may be entering back into _____ of antibiotics.
dark ages
term ESKAPE pathogens has been widely used to describe most _____.
debilitating hospital-acquired bacteria
23S rRNA mutations of 50@ (MLSB) mutations in the 23S rRNA is linked to a?
decreased antibiotic affinity
most antibiotics work by targeting metabolically active cells; in a biofilm, cells tend to have a ____ & thus, exhibit resistance to antibiotics. such cells are called ____.
decreased metabolic activity; persister cells
C-55 has to be _____ before it flips back across membrane & recharges, because phosphates carry negative charge & are not readily carried across membrane.
dephosphorylated
lysinylation: lysine residue added to a phospholipid by a multiple peptide-resistance factor (MprF) enzyme shifts the net charge from dianionic (2 negatively charged phosphates) to monocationic (2 positively charged amines); _____ negative charge on the phosphate neutralized by 2 amines; opposite charges attract, & like charges repel. resulting positive net charge repels ____ away from bacterial cell wall.
dianionic; daptomycin
many different semisynthetic derivatives of penicillin that differ in side chains have been derived, what are they?
different penicillins; ampicillin; amoxicillin; & methicillin
downside to live, attenuated vaccines?
difficult to make & dangerous for those w/ weakened immune systems, like the elderly
type of antibiotic sensitivity test often called the Kirby-Bauer method (disk diffusion test); involves a paper disk w/ a standardized quality; antibiotic generates a concentration gradient of antibiotic in agar.
diffusion method
using a 96-well microplate for _____ or the minimum inhibitory concentration (MIC) test: highest concentration of antibiotic added to column 1 & antibiotic was serially diluted by a factor of 2 down to column 10; column 11 contains positive control (either inhibited/killed bacteria) & column 12 includes _____ meaning media alone w/o any antibiotics. bacteria inoculated into plate, & plate is incubated over period of time, during which bacteria are either killed, growth inhibited, or unaffected.
dilution method; negative control
unit extruded thru the cytoplasmic membrane & polymerized into murein wall.
disaccharide pentamuropeptide
antibiotics are not developed; they're? *however, this definition may be confusing, since we have fully synthetic antibiotics today that aren't microbial products, yet they're still antibiotics.
discovered
use TB, malaria, & HIV as a model to determine ______ & ______.
disease burden & interventions
downside of inactive vaccines?
don't create long-lasting immunity
when bacteria exposed to stress (including antibiotics), can shift metabolism to become ____, leading to changes in surface, activating core signaling & initiating biofilm formation.
dormant
______ is now cited as primary source of waterborne disease outbreak in developed countries, due to establishment of opportunistic pathogens in pipe & water fixture biofilms.
drinking water
most important limitations of rational design screening platform understand penetration properties of molecule; if molecule can't enter cells, it's useless & will never reach its target(s). thus, enhancing _____ will stimulate rational drug design research. these modifications may include... - _____ of molecule - inhibition of _____ pumps of gram-negative bacteria
drug penetration; drug modification; efflux
if antibiotic not working in clinic, physicians increase concentration of drug as long as it's safe; in natural reservoir, if antibiotic loses effectiveness due to fitness cause, there's an evolutionary selection against that bacteria that produce ineffective antibiotics.
dynamic selection
STDs are ____, bc many are asymptomatic; estimated that 75% of all women & 50% of all men infected w/ chlamydia show no symptoms; these infections sit dormant for months/years, until something triggers emergence from their dormant state.
easily transmissible
of course, reporting to GLASS is still limited & depends on countries' _____.
economic status
PACCARB recommendation #1: require _____ accrediting bodies to include a model curriculum in IP&AS that's taught at all levels of healthcare & continuing worker education; incorporate existing recommended core competencies.
education/training
bacteria required defense mechanisms to protect themselves against antibiotics they produce; in order to do so, they have evolved membrane _____ that pump antibiotics out of cell, especially present in gram (-) bacteria; many of them are examples of intrinsic resistance.
efflux pumps
confer resistance to tetracyclines & chloramphenicols.
efflux pumps
in recent study, chlorhexidine, an antiseptic mouthwash component, induced expression of mutli-drug resistant _____.
efflux pumps
C-55-isoprenyl pyrophosphate flippase binds to _____, which gets modified w/ the additional sugar to become lipid II molecule; transport of lipid II facilitated by C-55-isoprenyl pyrophosphate flippase; flips across membrane & localized at periplasmic space.
lipid I
enzyme responsible for charging tRNA molecules w/ isoleucine.
isoleucyl-tRNA synthetase
protodrug metabolized into active form by Mtb catalase peroxidase enzyme that facilitates isoniazid fusion w/ NAD molecule; most commonly used antituberculosis drug.
isoniazid
toothbrushing "better than antibiotics," why?
it mechanically removes harmful biofilms
binds specifically to 30S subunit of the ribosome, leading to interference w/ initiation complex, misreading of mRNA; leads to arrest of protein synthesis; provided treatment option for already-streptomycin-resistant Mycobacterium tuberculosis.
kanamycin
due to _____, bacitracin only available topically.
kidney toxicity
why are antibiotics used as growth promoters?
known to increase animal weight, because antibiotics inhibit gut bacterial growth, which leads to increased energy uptake by animal. others say antibiotics kill pathogens, so animals don't have to mount the immune response & can channel that energy toward growth instead.
in 2013, FDA required that pharmaceutical companies do what?
label their products: not for growth promotion
turns out that Brucella feeds on elevated _____ inside of cells & Brucella can now utilize AAs that cannot enter mitochondria nor into TCA cycle. bc Brucella most likely feeds on elevated _____ in cells, inhibition of lactate production w/ small molecules completely abolished infection; limiting host resources can inhibit growth/replication of intracellular bacteria.
lactic acid
39% of all deaths related to AMR in Europe are due to bacteria that are resistant to _____.
last-reserve antibiotics (pan-resistance)
antibiotics can lead to decreased levels of porins; less porins at outer membrane = ?
less antibiotics getting in
we can use L-cyclopropylamine to fight off bacteria: _____ is an essential AA; therefore, we can't synthesize it - it comes from diet. bacteria do synthesize _____, so by inhibiting _____-synthesis pathway, bacteria are affected but humans aren't.
leucine
from Streptomyces lincolnensis (soil from Lincoln, Nebraska); 2 types of antibiotics: clindamycin (higher potency) & lincomycin; bind to 23S subunit of 50S bacterial ribosome; leads to bacteriostatic inhibition of protein synthesis.
lincosamides
antibiotics that target 50S ribosomal subunit?
lincosamides, macrolides, chloramphenicol, oxazolidinones, & streptogramins
type of enzymatic degradation (type of antibiotic inactivation); involves cutting of the antibiotic. such mechanisms of resistance are quite common, especially against cyclic antibiotics (glycopeptides, ansamycins (like rifampicins), or streptogramins).
linearization
these classes of membrane efflux pumps are powered by a proton gradient.
major facilitator class (MFC), small mutli-drug resistance class (SMR), & resistance-nodulation-division (RND)
excretions from animal farms enter wastewater & are used as?
manure
resistance to methicillin mediated by a mobile gene called _____ - encodes for low affinity penicillin-binding protein (PBP).
mecA
resistance to methicillin wasn't dependent on typical B-lactamases but was encoded by _____, a gene coding for PBP2a, a PBP homolog that exhibits low affinity for all clinically used B-lactam antibiotics.
mecA
one of the most common antibiotic resistance mechanisms employed by bacteria is the modification of the _____.
membrane charge
antibiotic sequestration: gram (-) bacteria have evolved a mechanism by which it secretes _____ that sequester membrane-disrupting antibiotics (e.g., colistin or polymyxin), preventing actual antibiotic from getting its target on cell membrane.
membrane vesicles
semisynthetic derivative of penicillin; narrow-spectrum B-lactam, meaning it targets only specific pathogens; it's resistant to cleavage by B-lactamases.
methicillin
in 1986, Beck et al. published study that described novel DNA material encoding something responsible for ____.
methicillin resistance
MRSA is _____ S. aureus.
methicillin-resistant
in humans, _____ is a drug that selectively binds DHFR & inhibits cellular division of rapidly dividing cells; used as immunosuppressant or cancer chemotherapeutic.
methotrexate
(a vancomycin antibiotic activated by anaerobic bacteria); ability to covalently & irreversibly bind to DNA placed this drug on the list of human carcinogens; induces cancer in animal models but acute exposure in humans has not been linked to cancer; rare instances, can cause Stevens-Johnson Syndrome.
metronidazole
antibiotic resistance is a term that's relative to antibiotic concentration that can kill bacteria in a Petri dish. this concentration is often referred to as ______. minimum concentration of an antibiotic required to completely inhibit bacterial growth.
minimal inhibitory concentration (MIC)
_____ test also called dilution method: type of antibiotic sensitivity test used to determine minimal concentration of antibiotic required to inhibit/kill bacteria. can be done either on solid or liquid media.
minimum inhibitory concentration (MIC)
aminoglycosides increase _____ frequency from 1-100 amino acids. *avg. bacterial protein of 300 AA's will have 3 mistakes.
mistranslation
AAs metabolized in _____.
mitochondria
location of ARG's on _____, such as plasmids, transposons, & integrons, makes the transfer of resistance possible & easy to achieve among bacteria w/ same or different origins.
mobile genetic elements (MGE's)
Forsberg identified multiple _____ that can explain mechanisms by which these genes jumped to human pathogens.
mobilization sequences
come from bacteria; characterized by a single 4-membered b-lactam ring; specifically target gram (-) bacteria like E. coli & Pseudomonas.
monobactams
anti-antibiotics are ____ defense mechanisms.
natural
antibacterial power pf penicillin can be persevered longer by _____.
neutralization
current guidelines on prophylactic use of antibiotics for prevention of IE in U.K.: insufficient evidence on benefits of a prophylactic antibiotic; _____ remains in effect for dental treatment for patients at high risk of IE.
no antibiotic prophylaxis recommendation
where presence of manmade antimicrobials raises selective pressure for antibiotic resistance; includes use of antibiotics in food animals such as poultry, beef, & pork; increasing concentration of antibiotics in environment, such as wastewater.
non-clinical ecosystem
what is most troublesome is the fact that prior to introduction of antibiotics, all B-lactamases were encoded on _____. somehow during intro of antibiotics, these antibiotic-resistant genes were able to jump onto plasmids that facilitate rapid horizontal gene transfer & further spread resistance.
non-mobile genomic DNA
most effective treatment of bacterial infections is when antibiotic MIC is ____ to humans. however, certain drugs are still administered at toxic concentrations.
non-toxic
the infection is susceptible to treatment if antibiotic MIC falls within concentration that is _____ to humans.
non-toxic *y-axis: bacterial survival *x-axis: drug concentration
providing necessary resources to maintain survival of host. e.g., replenishing fluids & electrolytes during diarrheal infections increase chances of survival & allow immune system to clear off infections.
nonimmune toleralizing approaches
infections contracted in healthcare setting (i.e., hospital, clinic, nursing home, etc.)
nosocomial or hospital-acquired infections (HAIs).
majority of automated antibiotic susceptibility systems utilize genomic data to detect pathogen-specific _____ or presence of ABR _____.
nucleic acids; genes
Forsberg found perfect ____ between ABR genes from soil bacteria compared to diverse human pathogens.
nucleotide identity
_____ mutations in the 16S rRNA has been linked to resistance of bacteria to both aminoglycoside & tetracycline antibiotics.
nucleotide substitution
type of enzymatic modification (type of antibiotic inactivation); involves addition of nucleotides.
nucleotidylation
aadB was the specific gene Forsberg found that encoded for this enzyme - a nucleotidyltransferase enzyme that covalently modifies antibiotics by addition of nucleotides to render them inactive.
nucleotidyltransferase
translation antibiotics that affect 30S subunit?
o Aminoglycosides o Tetracyclines
translation antibiotics that affect 50S subunit?
o Lincosamides o Macrolides o Chloramphenicol o Oxazolidinones o Streptogramins
times during our lives when immune system is still developing or not able to defend us as we age.
old & young
activation of silent operons: while there's no effective way of turning these genes on, one approach being developed is to clone entire _____ into different bacteria under inducible _____.
operons; promoters
patients w/ HIV & diabetes are predisposed to _____ pathogens.
opportunistic
Candida is a _____, meaning it can attack human bodies when given opportunities to thrive.
opportunistic pathogen
____ already resistant to ampicillin, kanamycin, gentamicin, & tetracycline.
oral bacteria
in 2012: CDC updates recommendations again in response to data suggesting the _____ is becoming less effective, & gonorrhea has become even harder to treat.
oral cephalosporin cefixime
2 main kinds of cephalosporins to treat gonorrhea?
oral drug cefixime & injection ceftriaxone
immune system of _____ patients is purposefully suppressed, allowing infections to set in, there are a number of other factors/conditions that compromise our defense mechanisms.
organ transplant
studies have shown that antibiotic-resistant E. coli is must less common in _____ raised animals than in conventional ones.
organically
humans did not develop antibiotic resistance, but bacteria naturally have developed counter-attack mechanisms against?
other microbes trying to kill them
gonorrhea so prone to antibiotic resistance, because?
our immune systems are not able to combat intracellular bacteria; antibiotics are only treatments, but the use of them sped up selection for ABR.
_____ of gram (-) bacteria provides permeability barrier that decreases ability of b-lactam antibiotics to target PBP; thus, they decrease but do not necessarily abolish effectiveness of b-lactam antibiotics.
outer membrane
gram (-) peptidoglycan layer is sandwiched between outer & cytoplasmic membranes, while peptidoglycan of gram-positive is on the _____ of the cell.
outside
boosting immune system not that easy, because _____ can lead to debilitating autoimmune diseases.
overactivity
inhibitors of protein synthesis that block the initiation step of mRNA translation; binds to 50S ribosomal subunit at earlier step compared to other ribosomal inhibitors & inhibits formation of initiation complex; prevents formation of ternary complex between mRNA ribosomal subunits & the tRNA charged w/ formylmethionine. e.g., linezoid.
oxazolidinones
repurposed drugs - initially developed as monoamine oxidase inhibitors for the treatment of depression; type of drug that targets 50S ribosomal subunit; prevents formation of ternary complex between mRNA ribosomal subunits & the tRNA charged w/ formylmethionine. e.g., linezoid.
oxazolidinones
Abraham & Chain's experiment: took E. coli extract & incubated w/ penicillin antibiotic; extract inactivated the penicillin & its ability to kill S. aureus; after additional experiments, thought that it had to be an enzyme that was responsible for deactivating the penicillin antibiotic - thought this, because enzymes get inactivated by heat; heated extract for 5 min. @ 90 degrees centigrade, & the enzyme was deactivated. could also inactivate enzyme by _____ - a protease that digests enzymes that renders them inactive, & the enzyme was also non-dialysable thru cellophane membrane; could precipitate w/ alcohol, but activity was lost during precipitation; also, @ lower pH, enzyme loses ability to cleave penicillin. named enzyme ______ - destroys penicillin.
papain; penicillinase
(transpeptidase) enzyme involved in cell wall synthesis; catalyze cross-linking between adjacent sugar glycan chains by removing terminal D-alanine residue from one of peptidoglycan.
penicillin-binding protein, PBP
few years after intro of penicillin, new strain that has been resistant to penicillin (_____) emerged.
penicillin-resistant S. aureus
in 1977, the FDA banned the use of _____ & _____; this proposal was opposed by industry & drug-makers.
penicillin; tetracycline
in 1980s, gonorrhea resistance to _____ & _____ grows, & they were no longer recommended to treat the infection.
penicillin; tetracycline
type of antibiotic target modification that involves the restructuring of bacterial cell wall conferring antibiotic resistance; its target modification is vancomycin resistance against glycopeptide antibiotics (e.g., vancomycin).
pentapeptide modification
non-B-lactam cell wall synthesis inhibitors?
peptides, cycloserine, fosfomycin
bacteria, specifically Staphylococcus, develop a smart strategy of deploying fake antibiotic molecules that protect antibiotic targets by sequestering antibiotics. this is the overproduction of _____.
peptidoglycan
polymer whose molecules are cross-linked by amino acids to form protective grid over cell membrane; gives cell shape & strength; counteracts internal osmotic pressure from cytoplasm; w/o _____, the cell would rupture & die.
peptidoglycan
to increase rigidity/stability of cell wall, adjacent pentapeptide chains that are sitting on NAM opposite to each other are cross-linked into a structure known as _____ & _____.
peptidoglycan peptide; sugar glycan
4th step of bacterial translation; first AA joins to 2nd by a peptide bond, & first tRNA is released from E site.
peptidyl transfer
enzyme that facilitates peptide bond formation between 2 adjacent amino acids, located at P & A site of ribosomes.
peptidyl transferase
in B-lactamase testing, more specifically modified hodge test (MHT), the plate contains 4 strains: 1: _____ - producer of B-lactamases (K. pneumoniae ATCC BAA-1705). o 2: _____ - no B-lactamase activity (K. pneumoniae ATCC BAA- 1706). o 3: _____ - unknown for production of B-lactamases. o 4: _____ (sensitive to carbapenems - E. coli ATCC 25922). indicates presence of B-lactamases in test strain by affecting zone of inhibition. plate contains a carbapenem antibiotic. _____ producer inhibits carbapenem antibiotic that diffuses from disk, which allows indicator strain to grow, & disk w/ carbapenem is placed in middle.
positive control; negative control; test strain; indicator strain; carbapenemase
marked by sulfa drugs & penicillin.
primordial states
targeting human cells to modulate bacterial uptake: treated cells before & after infection; if drug was inhibiting bacterial entry, it will be effective only when used _____ to infection. e.g., _____.
prior; disulfiram
WHO also uses prioritization for antibiotics; antibiotics are _____ if high absolute number of people, or high proportion of use in patients w/ serious infections in healthcare settings affected by bacterial diseases for which the antimicrobial class is the sole or one of few alternatives to treat serious infections in humans.
prioritization criterion 1 (P1)
WHO also uses prioritization for antibiotics; antibiotics are _____ if high frequency of use of antimicrobial class for any indication in human medicine, or else high proportion of use in patients w/ serious infections in healthcare settings, since use may favor selection of resistance in both settings.
prioritization criterion 2 (P2)
WHO also uses prioritization for antibiotics; antibiotics are _____ if antimicrobial class used to treat infections in people for which there is evidence of transmission of resistant bacteria (e.g., non-typhoidal Salmonella & Campylobacter spp.) or resistance genes (high for E. coli & Enterococcus spp.) from non-human sources; relates to transmission.
prioritization criterion 3 (P3_
a drug that's not active in its original form, but it's made active by metabolism conducted in the body.
protodrug
most sensitive strains to penicillin?
pyogenic cocci
to combat biofilm infections: quorum sensing is essential for bacteria to coordinate biofilm production & its maintenance; disruption of quorum sensing by ____ can inhibit biofilm infection when combined w/ other conventional antibiotics.
quenching enzymes
10 FDA-approved were withdrawn from U.S. make 1990-2000; 3 of these drugs were ____ antibiotics.
quinolone
antibiotics characterized by 4-quinolone bicyclic ring; chemotherapeutic bactericidal drugs, eradicating bacteria by inhibiting DNA replication; inhibit bacterial DNA gyrase or topoisomerase IV enzyme, thereby inhibiting DNA replication & transcription; topoisomerase II also a target for variety of _____-based drugs.
quinolones
class of antibiotics that inhibits bacterial replication?
quinolones
function at level of DNA replication & DNA transcription (DNA gyrase) - known o inhibit type II isomerases including gyrases & topoisomerase IV; characterized by 4-_____ bicyclic ring; antimicrobial activity (Nalidixic acid) discovered in 1963 by George Lesher & colleagues (team was pursuing discovery of new chemical entities against malaria & accidentally discovered antibacterial property of Nalidixic Acid).
quinolones
physical barrier between bacteria & outside environment; the barrier protection from antibiotics, however, is not as strong as once thought. e.g., ____ rapidly diffuse into Pseudomonas or Klebsiella biofilms.
quinolones
disrupt intracellular signaling between bacteria to block coordinated tissue invasion & can interfere w/ bacteria's ability to become pathogenic.
quorum sensing inhibitors
known to be transported out of cells via efflux pumps.
quorum sensing molecules
- immediate results. - proper antibiotic prescribed. - low potential for resistance.
rapid diagnostics
screening platform for species-specific compounds: _____ can identify resistant isolates.
rapid diagnostics
is the infection bacterial or viral? _____ include strep test, flu test, etc.
rapid tests
type of MOA that targets antibiotic availability; generally thru reduced production or modification of porins.
reduced permeability to antibiotics
phenomenon commonly observed in drinking water distribution systems, in which ABR microorganisms grow in the pipes of water distribution systems, altering the quality of recycled water as it gets distributed.
regrowth
antibiotic resistance assessment encompasses diagnostic tools that identify _____ & determine _____ to antibiotics. while surveillance is a bird's eye view of the problem, the assessment is a close-up investigation of the mechanism.
resistance mechanisms; sensitivity
2-component regulatory system: studies of promoter region revealed that deletion of BlrB DNA-binding site attenuated expression of B-lactamases - suggesting BlrB is a _____.
response regulator
tetracyline binds _____ to the top of 30S ribosomal subunit; binding site overlaps partially w/ aminoacyl-tRNA binding site, leading to tRNA dissociation from ribosome consequently blocking translation.
reversibly
prokaryotic subunits of ribosome are made of?
ribosomal RNA & proteins *function same as eukaryotes, but structure is different.
macrolides target _____ & inhibit _____.
ribosome; protein synthesis
____ binds directly to bacterial RNA polymerase & inhibits its function.
rifampicin
drugs specifically bind to & inhibit transcription of DNA-dependent RNA polymerases (enzymes responsible for transcription); from soil bacteria Nocardia mediterranei; belongs to group ansamycins; broad-spectrum antibiotic effective against mycobacteria, gram (+), gram (-), & most anaerobes; binds to bacterial RNA polymerase & prevents RNA synthesis; depending on concentration, can either be bactericidal or bacteriostatic; binds in path of elongating RNA molecule by simple steric block.
rifampin
causes neurotoxicity?
rifampin, isoniazid, & quinolones
deactivation by enzymatic linearization includes _____, which is an enzyme that linearizes rifampicin.
rifamycin monooxygenase (ROX)
cells began to accumulate higher concentration of internal osmolytes & therefore, were at risk of rupture. solution - development of ____ that completely covered cell; was strong & able to aid cell in resisting turgor pressure.
sacculus
covering fabric of bacterial cells that is composed of a large number of covalently linked disaccharide muropeptides.
sacculus
2,000 years later after Hippocrates' recommendation to use Willow Tree bark as fever reducer, _____ (also known as aspirin) was isolated as Willow Tree bark active ingredient responsible for anti-inflammatory & fever-reducing properties.
salicylic acid
plant-derived drug isolated from Angels' Trumpet.
scopolamine (motion sickness medication)
antibiotics are regarded as _____ metabolites.
secondary
disruption of normal microbiota can lead to _____ infections (e.g., vaginitis, other fungal infections, C. difficile).
secondary
compounds that aren't required for normal growth or proper "primary" function of the organism.
secondary metabolites
thought that antibiotic resistance evolved from ____ somehow acquired by other bacterial species that don't produce antibiotics themselves.
self-defense mechanisms
type of antibiotic that's derived from naturally derived antibiotics (e.g., amoxicillin).
semi-synthetic
properties of antibiotics (or any other drug) can be modified by generating _____, usually by slightly modifying side chains.
semi-synthetic derivatives
ABR testing requires _____; w/o it, results would vary between labs - mainly pertains to clinical labs. data would be difficult to interpret.
standardization
many _____ species are nonpathogenic & form part of commensal human microbiome of mouth, skin, intestine, upper respiratory tract.
streptococcal
isolated from soil bacteria, Streptomyces, during "Golden Age" of antibiotics; mixture of 2 structural distinct compounds - type A & type B, produced by Streptomyces at a 70:30 ratio; Streptogramin A & Streptogramin B - bacteriostatic individually, but bactericidal when combined (potency increases 100x).
streptogramins
isolated from soil bacteria, Streptomyces; mixture of 2 structural distinct compounds - type A & type B, produced by Streptomyces at a 70:30 ratio; bacteriostatic individually, but bactericidal when combined (potency increases 100x).
streptogramins
a trisaccharide w/ 3 amino groups highlighted in yellow; (first effective medicine for tuberculosis) - discovered in 1944 by Selman Waksman, who pioneered isolation of aminoglycosides from Streptomyces.
streptomycin
aminoglycosides include?
streptomycin, neomycin, kanamycin, & gentamicin.
antigen could be proteins/polysaccharides; vaccines can prompt very specific responses.
subunit vaccine
only made from one part of pathogen called antigen, which is the ingredient that triggers immune response.
subunit vaccine
type of sulfa drug that inhibits dihydropteroate synthase, which is the enzyme responsible for synthesis of dihydropteroate from dihydropterin pyrophosphate.
sulfamethoxazole
combination therapies target what pathway?
sulfamethoxazole/trimethoprim
drug that mimics para-aminobenzoate; structural homolog that mimics PABA & binds to dihydropteroate synthase, which is responsible for conversion of dihydropterin pyrophosphate to dihydropteroate, inhibiting its function.
sulfanilamide
1930s: _____ introduced as treatment against gonorrhea, but decade later, nearly all cases of gonorrhea were resistant to sulfa drugs due to single point mutation in folP gene that cods for DHPS.
sulfonamides
class of antibiotics that inhibits folic acid synthesis pathway?
sulfonamides
inhibit folic acid synthesis pathway by binding & inhibiting specific enzyme called dihydropteroate synthase (DHPS); includes trimethoprim.
sulfonamides
according to WHO, the purpose of _____ is to better understand/respond to antimicrobial resistance patterns & key drivers, information about AMR incidence, prevalence, & trends.
surveillance
purpose of _____ on AMR: to determine scope of problem; formulate effective response to AMR & monitor effectiveness of response.
surveillance
collects basic demographic, clinical, epidemiological, & microbiological info from patients.
surveillance Site
when Griffith injected mice w/ bacteria not encapsulated; these were not virulent, & mice ____.
survived
due to Typhoid Mary story, perhaps it's better to be _____ to an infection but only if there are treatment options available.
symptomatic
combination therapies enhance efficacy (provides a _____ effect): streptogramin A & B.
synergistic
the combined potency of a combination of drugs is much higher than the sum of their individual potencies.
synergistic effect
type of antibiotic that's fully synthesized in a "test tube" (e.g., quinolone).
synthetic
to combat biofilm infections: pysical disruption of biofilms like ____ & ____ - most commonly known approaches to biofilm disruption.
toothbrushin & dental cleaning
infection manifests clinical resistance when MIC of a specific antibiotic is _____ to humans & falls within _____ window. here, the infection can no longer be treated w/ that specific antibiotic. bacteria, as opposed to being susceptible, are now referred to as resistant to that specific antibiotic.
toxic
cancer patients have their immune system wiped out by _____ leaving affected individual prone to a range of bacterial infections.
toxic chemotherapy
- takes patient specimen; takes days. - non-specific antibiotic prescription. - high potential for resistance.
traditional diagnostics
synthetic antibiotic that arrests cell cycle (bacteriostatic) but doesn't kill cells; 100k-fold selectivity for bacterial DHFR over human DHFR; § broad-spectrum antibiotic commonly prescribed to treat MRSA (always in combination w/ other antibiotics, specifically antibiotics that inhibit folic acid synthesis pathway); targets dihydrofolate reductase (DHFR), which disrupts production of tetrahydrofolate (directly used in nucleotide synthesis).
trimethoprim
2004: CDC no longer recommends fluoroquinolones as treatment against gonorrhea for men who have sex w/ men in the U.S. t/f?
true
ABR is dynamic between aquaculture & agriculture reservoirs; resistance genes are constantly selected for/migrating between reservoirs, whether these reservoirs be natural or reservoirs that were selected for by use of manmade antibiotics. t/f?
true
ABR is ubiquitous; exists everywhere, even in space. t/f?
true
AMR can affect anyone, of any age, in any country. t/f?
true
AMR is a worldwide issue, t/f?
true
AMR occurs naturally, t/f?
true
Alexander Fleming warned about making microbes resistant to penicillin the lab by exposing them to insufficient concentrations (not enough to kill bacteria). t/f?
true
ESKAPE infectious now occur that are resistant to all current antimicrobial/antibacterial options, t/f?
true
FDA banned use of antibiotic agents in personal hygiene products, t/f?
true
U.S. hasn't seen treatment failure when using today's dual treatment for gonorrhea, but resistance is rising, & pipeline for new drugs is shrinking. t/f?
true
alanylation: positively charged membrane repels cationic compounds. t/f?
true
almost all soil bacteria are unculturable, nonpathogenic to humans. even if they get into our bodies, our immune system (if functioning well) will get rid of these bacterial species immediately; chances are really low that these resistant genes would jump onto pathogenic bacteria, & on top of it, be selected by misuse of antibiotics. t/f?
true
quinolones kills cells by inhibiting ____ (specifically, gyrases & topoisomerase IV).
type 2 topoisomerases
the _____, _____, & _____ are issues w/ antibiotic usage that contribute to AMR.
underuse, use, & overuse
all the work that pharmaceutical, medical, & scientists put together to develop new antibiotic is destryoed by?
underuse, use, & overuse of antibiotics.
in B-lactamase testing, more specifically modified hodge test (MHT), _____shows a disrupted zone of inhibition, indicating that it produces/secretes B-lactamases that degrade B-lactam antibiotics (in this example, carbapenem) & allows growth of indicator strain.
unknown strain (#3)
estimated that 10-90% of antibiotics are excreted in _____, leading to constantly increasing concentration of antibiotics in aquatic environments.
urine/feces
the first two WHO prioritization criteria are related to number of potential ______; _____ of use; & selection for _____.
users; frequency; resistance
_____ are a good example of adaptive immunity; demonstrates how adaptive immunity can be established using antigens present in _____.
vaccines
difficult to develop & not suitable for all infections.: § Prevent a disease § Target immune system § Long-term effect § Eradicate disease from society § No environmental pollution
vaccines
host-directed antimicrobial therapy @ organism level: targets immune system (i.e., _____).
vaccines
trigger body's adaptive immune system w/o exposing humans to full-strength of the disease.
vaccines
synthesis of D-Ala-D-lactate in S. aureus only occurs after exposure of bacteria to low concentrations of vancomycin; this form of resistance results from conjugation transfer of a plasmid containing the _____.
vanA operon
in 2-component regulatory system, this is a dehydrogenase that reduces pyruvate to D-lac.
vanH
in 2-component regulatory system, this is a transcriptional activator of the vanHAX operon.
vanR
in 2-component regulatory system, this is a membrane-associated sensory kinase; detects presence of glycopeptide & sends signal to vanR that activates transcription of vanHAX.
vanS
in 2-component regulatory system, this is a dipeptidase that hydrolyzes/breaks D-Ala-D-Ala bond.
vanX
S. aureus (VRSA) is able to substitute lactate for alanine (peptide ---> ester bond) - this is complete _____ resistance.
vancomycin
a glycoprotein isolated from actinobacteria; synthesized in non-ribosomal fashion by non-ribosomal peptide synthase; twice the size of gram (-) porins, so only works on gram (+) (mostly true for all other peptide antibiotics as well); effective against MRSA, making it a last-reserve antibiotic; caps D-Ala-D-Ala & prevents its incorporation into peptidoglycan & subsequent cross-linking; good for gram (+) resistant to penicillin/methicillin.
vancomycin
used in gram (+) bacteria that are resistant to penicillin/methicillin (i.e., S. aureus); "last resort" antibiotic for MRSA; caps D-Ala-D-Ala & prevents its incorporation into peptidoglycan & subsequent crosslinking; lethal inactivation of peptidoglycan crosslinking, despite the resistance to penicillin & methicillin.
vancomycin
very potent antibiotic, but because of methicillin's high potency, ____ wasn't used for Staph infections until late 1980's when MRSA infections were getting out of control.
vancomycin
types of peptide cell wall synthesis inhibitors?
vancomycin (glycopeptide) & bacitracin (cyclic peptide)
VISA stands for?
vancomycin intermediate-resistance S. aureus
HA-MRSA resistance against _____ or _____ has not been detected yet.
vancomycin or linezoid
______ is a growing concern for gram-positive S. aureus resistance.
vancomycin resistance
