Micro chapter 10
the presence of the antimicrobial agent does not produce resistance but instead selects for the replication of resistant cells that were already present in the population.
"alphabet soup" of resistant pathogens and diseases plague health care professionals: MRSA, VRSA, VISA, VRE, MDR-TB, AND XDR-TB
30S and 50S subunits of a prokaryotic ribosome play a role in the initiation of protein synthesis, in codon recognition and in the docking of tRNA-amino acid complexes
50S subunit contains the enzymatic portion that actually forms peptide bonds
Quinolones target which of the following molecules? -DNA gyrase
A(n) __________ is defined as an antimicrobial substance that is produced naturally by an organism. -antibiotic
A Kirby-Bauer test is used to classify a pathogen as synergistic or resistant to a particular antimicrobial. -False
All of the following are mechanisms of action associated with drugs that inhibit cell wall synthesis EXCEPT __________. -they dismantle existing peptidoglycan molecules
aminoglycosides and tetracyclines target 30S ribosomal subunits
Aminoglycosides such as streptomycin and gentamicin change the shape of the 30S subunit making it impossible for the ribosome to read the codons of the mRNA correctly
other aminoglycosides and tetracyclines block the tRNA docking sites which then prevents the incorporation of the additional amino acids into growing polypeptide
Chloramphenicol and similar drugs block the enzymatic site of the 50S subunit which prevents translation
to effectively treat infectious diseases, physicians must know which antimicrobial agent is most effective against a particular pathogen- to ascertain the efficacy of antimicrobials, microbiologists conduct a variety of tests, including diffusion susceptibility tests, the minimum inhibitory concentration test, and the minimum bactericidal concentration test.
Diffusion susceptibility tests also known as the Kirby-Bauer tests involve uniformly inoculating a Petri plate with a standardized amount of the pathogen in question. then small disks of paper containing standard concentrations of the drugs to be tested are firmly arranged on the surface of the plate. the plate is incubated and the bacteria grow and reproduce to form a "lawn" everywhere expect the areas where effective antimicrobial drugs diffuse through the agar. after incubation the plates are examined for the presence of a zone of inhibition- that is a clear area where bacteria do not grow.
oral route is simplest-it requires no needles and is self administered, the drug concentrations achieved in the body are lower than occur via other routes of administration
IM administartion via a hypodermic needle allows a drug to diffuse slowly into the many blood vessels within muscle tissue, but the concentration of the drug in the blood is never as high as that achieved by IV administration which delivers the drug directly into the bloodstream through either a needle or a catheter.
A drug that is effective against a small number of pathogens is called a(n) __________ drug. -narrow-spectrum
In which of the following categories of antimicrobial drugs are the fewest drugs available? -antiviral
The path a typical antimicrobial drug must take to affect a microbe: the drug must cross the cells wall then cross the cytoplasmic membrane to enter the cell, there the antimicrobial binds to it's target molecule. only then can it inhibit or kill the microbe.
Microbes gain resistance by blocking some point in this pathway. there are 5 mechanism of resistance: 1.resistant cells may produce an enzyme that destroys or deactivates the drug- this common mode of resistance is exemplified by beta-lactamases (penicillinases) 2. resistant microbes may slow or prevent the entry of the drug into the cell. this mechanism typically involves changes in the structure or electrical charge of the cytoplasmic membrane proteins that constitute channels or pores.---gram neg bacteria are called porins 3. resistant cells may alter the target of the drug so that the drug either cannot attach to it or binds it less effectively-this form of resistance is often seen against antimetabolites (such as sulfonamides) and against drugs that thwart protein translation(such as erythromycin) 4. resistant cells may alter their metabolic chemistry, or they may abandon the sensitive metabolic step altogether. 5.resistant cells may pump the antimicrobial out of the cell before the drug can act. so called efflux pumps which are typically powered by ATP and are often able to pump more than one type of antimicrobial from a cell. some microbes become multi-drug resistant by utilizing resistance pumps 6.bacteria within biofilms resist antimicrobials more effectively that free-living cells. biofilms retard diffusion of the drugs and often slow metabolic rates of species making up the biofilm. lower metabolic rates reduce the effectiveness of anti- metabolic drugs. 7. some resistant strains of bacterium Mycobacterium tuberculosis have a novel method of resistance against fluoroquinolone drugs that bind to DNA gyrase. these strains synthesize an unusual protein that forms a negatively charged, rodlike helix about the width of a DNA molecule. This protein called MfpA protein binds to DNA gyrase in place of DNA, depriving fluoroquinolone of it's target site. this is the first method of antibiotic resistance that involves a decoy to protect the target of an antimicrobial drugs rather than say changing the target or deactivating the drug. MfpA a decoy to protect probably slows down cellular division of M. tuberculosis but that is better for the bacterium that being killed.
lincosamides, streptogramins and macrolides bind to a different portion of the 50S subunit, preventing movement of the ribosome from one codon to the next, as a result, translation is frozen and protein synthesis is halted
Mupirocin is a unique drug that selectively binds to the bacterial tRNA that carries the amino acid isoleucine... it does not bind to any of the eukaryotic tRNA molecules-binding prevents the incorporation of isoleucine into polypeptides, effectively crippling the bacterium's protein production-prescribed in topical creams to treat skin infections
Bacteria of the genus Mycobacterium notably the agents of leprosy and tuberculosis are characterized by unique, complex cells walls that have a layer of arabinogalactan-mycolic acid in addition to the usual pepeidoglycan of bacteria cells
Mycobacteria typically reproduce only every 12-24 hours in part because of the complexity of their cell walls, so antimicrobial agents that act against mycobacteria must be administered for months or even years to be effective.
Actinomycin binds to DNA and effectivley blocks DNA synthesis and RNA transcription not only in bacterial pathogens but in their hosts as well.. generally drugs of this kind are not used to treat infections, though they are used in research of DNA replication and may be used carefully to slow replication of cancer cells.
Quinolones including fluoroquinolones which are unusual because they are active against prokaryotic DNA specifically. they inhibit DNA gyrase an enzyme necessary for correct coiling and incoiling of replication bacterial DNA, they typically have little effect on eukaryotes or viruses.
Which of the following cellular structures or molecules is the most SIMILAR in both bacteria and humans? -DNA
Some bacteria use antibacterial proteins called __________ to inhibit the growth of other bacterial strains. -bacteriocins
Why are some drugs that inhibit protein synthesis in bacteria also harmful to humans? -Eukaryotic mitochondria have 70S ribosomes.
The Etest combines elements of a diffusion susceptibility test and an MIC test. -true
Tetracyclines inhibit which of the following? -protein synthesis
The lowest concentration of a drug that results in killing of susceptible bacterial cells is the MIC. -false
Which of the following groups of microorganisms is a source of common antibiotics? -bacteria and fungi
The oral route of drug administration is best because it is the simplest route. -False
Bacterial cells may acquire drug resistance by which of the following mechanisms? -
The smallest amount of an antimicrobial drug that will inhibit growth and reproduction of a microbe is expressed as the __________. -minimum inhibitory concentration
Why are viruses more susceptible to nucleotide analogs than their host cells? -Viruses replicate their nucleic acid more rapidly than host cells do.
The use of microorganisms for health benefits is a field of study known as __________. -probiotics
Broad-spectrum antimicrobial drugs are more desirable than narrow-spectrum drugs. -false
Which of the following does NOT block the formation of folic acid in bacteria? -metronidazole
it has been shown that horizontal gene transfer most often by conjugation and less often by transformation, accounts for the spread of antimicrobial resistance among the densely growing cells of biofilms.
a given pathogen can acquire resistance to more than one drug at a time, esp when resistance is conferred by R plasmids, which are exchanged readily among bacterial cells.
microbial antagonism reinforces the body's defense by limiting the ability of pathogens to colonize the skin and mucous membranes
a woman using erythromycin to treat strep throat could develop vaginitis resulting from the excessive growth of Candida albicans
Trimethoprim, another antimetabolic agent also interferes with nucleic acid synthesis-instead of binding to the enzyme that converts PABA to dihydrofolic acid, trimethoprim binds to the enzyme involved in the conversion of dihydrofolic acid to THF, the second step in this metabolic pathway.
after attachment to a host cell, viruses must penetrate the cell's membrane and be uncoated to release viral genetic instructions and assume control of the cells metabolic machinery.
a consistant supply of proteins is vital for the active life of a cell
all cells including human cells use ribosomes to translate proteins using information from messenger RNA templates that drugs could selectively target differences related to protein synthesis
other antimicrobials such as vancomycin obtained from Amycolatopsis orientalis and cycloserine, a semisynthetic, disrupt cell wall formation in a different mannar........ they directly interfere with particular alanine-alanine bridges that link that NAM subunits in many gram positive bacteria-lack alanin-alanin crossbridges are naturally resistant to these drugs
all these drugs prevent bacteria from increasing the amount of cell wall material but have no effect on existing peptidoglycan, they are effective only on bacterial cells that are growing or reproducing, dormant cells are unaffected
the lowest concentration of drug for which no growth occurs in the subcultures is the minimum bactericidal concentration (MBC)
an adequate amount of an antimicrobial agent must reach a site of infection if it is to be effective
selective toxicity
an effective antimicrobial agent much be more toxic to a pathogen than to the pathogens host
synthetic drugs
antimicrobials that are completely synthesized in a laboratory
whenever differences exist between the metabolic processes of a pathogen and its host, antimetabolic agents can be effective
atovaquone interferes with electron transport in protozoa and fungi, heavy metal such as arsenic, mercury, and antimony which inactivates enzymes, agents that disrupt tubulin polymerization and glucose uptake by many protozoa and parastitic worms, drugs that block the activation of viruses and metabolic antagonists such as sulfanilamide, the first commercially available antimicrobial agent
magic bullets
bind to receptors on germs to bring about their death while ignoring host cells, which lacked the receptor molecules
a cell wall protects a cell from the effects of osmotic pressure
both pathogenic bacteria and fungi have cell walls which animals and humans lack
broad-spectrum-effective against many different kinds of pathogens ex: tetracycline acts against many different kinds of bacteria including gram neg, gram pos, chlamydias, and rickettsias, it is considered a broad spectrum antibiotic--- on the other hand penicillin has narrower spectrum of action than tetracycline
broad spectrum antimicrobials can open the door to serious secondary infections by transient pathogens or superinfections by members of the normal microbiota unaffected by the antimicrobial--- this results b/c the killing of normal microbiota reduces microbial antagonism, the competition b/t normal microbes and pathogens for nutrients and space.
some fungi and bacteria commonly produce antibiotics, most of these chemicals are not effective for treating diseased because they are toxic to humans and animals, are too expensive, are produced in minute quantities or lack adequate potency
characteristics that ideal antimicrobial agents to treat an infection or disease would be one that has all these characteristics: 1. readily available 2. inexpensive 3. chemically stable (so that it can be transported easily and stored for long periods of time) 4. easily administered 5. nontoxic and nonallergenic 6. selectively toxic against a wide range of pathogens
semisynthetic antimicrobials
chemically altered antibiotics that are more effective, longer lasting, and easier to administer than naturally occurring antibiotics
drugs
chemicals that affect physiology in any manner such as caffeine alcohol and tobacco
Paul Ehrlich proposed the term chemotherapy
chemotherapy-describe the use of chemicals that would selectively kill pathogens while having little or no effect on a patient
Multiple-drug-resistant pathogens(superbugs) are resistant to 3 or more types of antimicrobial agents.
cross resistance-resistance to one antimicrobial agent may confer resistance to similar drugs typically occurs when drugs are similar in structure
antimicrobial agents
drugs for treating infections
chemotherapeutic agents
drugs that act against disease ex are anticancer drugs
viruses utilize their host cells enzymes and ribosomes to metabolize and replicate
drugs that are effective against viral replication are likely toxic to the host as well
if all antimicrobials diffused at the same rate, then a larger zone of inhibition would indicate a more effective drug
drugs with low molecular weights generally diffuse more quickly and so might have a larger zone of inhibition than a more effective but larger molecules
other drugs that block protein synthesis are antisense nucleic acids. these RNA or single stranded DNA molecules are designed to be complementary to specific mRNA molecules of pathogens---block ribosomal subunits from attaching to that mRNA with no effect on human mRNA
fomivirsen is the first of this class of drugs to be approved-it inactivates cytomegalovirus and is used to treat eye infection
Oxazolidinones are antimicrobial drugs that work to stop protein synthesis by blocking initiation of translation-used as a last resort in treating infections of gram positive bacteria resistant to other antimicrobials including vancomycin and methicillin resistant staphylococcus aureus
gramicidin disrupt the cytoplasmic membrane of a targeted cell often by forming a channel through the membrane, damaging its integrity. this is also the mechanism of action of a group of antifungal drugs called ployenes. the polyenes nystatin and amphotericin B are fungicidal because they attach to ergosterol, a lipid constituent of fungal membranes in the process disrupting the membrane and causing lysis of the cell.
PABA, sulfonamides compete with PABA moleucules for the active site of the enzyme involved in the production of dihydrofolic acid this competition leads to a decrease in the production of THF and thus of DNA and RNA. the end result of sulfonamide competition with PABA is the cessation of cell metabolism, which leads to cell death
humans don't synthesize THF from PABA instead we take simple folic acids found in our diets and convert them into THF as a result human metabolism is unaffected by sulfonamides.
drugs that disrupt normal microbiota and their microbial antagonism of opportunistic pathogens may result in secondary infections
in instances when a member of the normal microbiota is not affectd by a drug it is an opportunistic pathogen and can overgrow causing a disease.
not all pathogens are equally sensitive to a given therapeutic agent individuals cells can acquire such resistance in two ways: 1. through new mutations of chromosomal genes OR by acquiring resistance genes on extrachromosomal pieces of DNA called R plasmids via the processes of horizontal gene transfer-transformation, transduction, or conjugation.
in the absence of an antimicrobial drug, resistant cells are usually less efficient than their normal neighbors because they must expend extra energy to maintain resistance genes and proteins. under these circumstances resistant cells remain the minority in a population because they reproduce more slowly. when an antimicrobial agent is present, the majority of cells are inhibited or die while the resistant cells continue to grow and multiply, often more rapidly because they then face less competition. the result is that resistant cells soon replace the sensitive cells as the majority in the population
beta-lactams inhibit peptidoglycan formation by irreversibly binding to the enzymes that cross link NAM subunits
in the absence of correctly formed peptidoglycan, growing bacterial cells have weakened cells walls that are less resistant to the effects of osmotic pressure.
PABA is crucial in the synthesis of nucleotides required for DNA and RNA synthesis
many organisms including some pathogens enzymatically convert PABA into dihydrofolic acid and then dihydrofolic acid into tetrahydrofolic acid (THF) a form of folic acid that is used as a coenzyme in the synthesis of purine and pyrimidine nucleotides
Clofazimine binds to the DNA of Mycobacterium leprae that causative agent of leprosy, and prevents normal replication and transcription---it is also used to treat tuberculosis and other mycobacterial infections.
many pathogens particularly viruses must attach to their hosts cells via the chemical interaction between attachment proteins on the pathogen and complementary receptor proteins on a host cell. attachment of viruses can be blocked by peptide and sugar analogs of either attachment or receptor proteins which viruses can neither attach to nor enter their host's cells- the use of such substances are called ATTACHMENT ANTAGONISTS EX are arildone and pleconaril are antagonists of the receptor of polioviruses and some cold viruses, they block attachment of these viruses and deter infections
Pyrazinamide disrupts transport across the cytoplasmic membrane of Mycobacterium tuberculosis the pathogen uniquely activates and accumulates the drug pyrazinamide is most effective against intracellular, nonreplicating bacterial cells change the permeability of cell membranes of several types of parasitic worms
metabolism is the sum of all chemical reactions that take place within an organism
azoles such as fluconazole and allylamines such as terbinafine are the two other classes of antifungal drugs that disrupt cytoplasmic membranes. they act by inhibiting the synthesis of ergosterol without ergosterol the cells membrane does not remain intact and the fungal cell dies. azoles and allylamines are generally harmless to humans because human cells do not manufacture ergosterol
most bacterial membranes lack sterold so these bacteria are naturally resistant to ployenes, azoles, and allylamines-however there are other agents that disrupt bactrial membranes ex is polymyxin, produced by Bacillus polymyxa polymyxin is effective against gram negative bacteria particularly Pseudomonas but because it is toxic to humans kidneys, it is usually reserved for use against external pathogens that are resistant to other antibacterial drugs
spectrum of action- the number of different kinds of pathogens a drug acts against
narrow-spectrum- drugs that work against only a few kinds of pathogens
fungal cells walls are composed of various polysaccharides containing a sugar 1,3-D-glucan that is not found in mammalian cells
new class of anitfungal drugs called echinocandins among them caspofungin inhibit the enzyme that synthesizes glucan without glucan, fungal cells cannot make cell walls, leading to osmotic rupture
diffusion susceptibility tests enable scientists to classify pathogens as susceptible, intermediate, or resistant to each drug
once scientistis identify an effective antimicrobial agent, they quantitatively express it's potency as a minimum inhibitory concentration (MIC) often using the unit ug/ml. MIC is the smallest amount of the drug that will inhibit growth and reproduction of the pathogen. the MIC can be determined via a broth dilution test in which a standardized amount of bacteria is added to serial dilutions of antimicrobial agents in tubes or wells containing broth after incubation, turbidity(cloudiness) indicates bacterial growth, lack of turbidity indicates that the bacteria were either inhibited or killed by the antimicrobial agent
nucleotide and nucleoside analogs are most often used against viruses because viral DNA polymerases are tens to hundreds of times more likely to incorporate these nonfunctional nucleotides into nucleic acids than is human DNA polymerase. complete viral nucleic acid synthesis is more rapid than cellular nucleic acid synthesis.
other antimicrobial agents function by binding to an inhibiting the action of RNA polymerases during the synthesis of RNA from a DNA template. Rifampin bind more readily to prokaryotic RNA polymerase than to eukaryotic RNA polymerase as a result rifampin is more toxic to prokaryotes than to eukaryotes. Rifampin is used primarily against M. tuberculosis and other pathogens that metabolized slowly and thus are less susceptible to antimicrobials targeting active metabolic processes.
the major structural component of a bacterial cell wall is it's peptidoglycan layer
peptidoglycan is a huge macromolecule composed of polysaccharide chains of alternating NAG and NAM molecules that are cross linked by short peptide chains extending between NAM subunits to enlarge or divide a cell must synthesize more peptidoglycan by adding new NAG and NAM subunits to existing NAG-NAM chains and the new NAM subunits must then be bonded to neighboring NAM subunits
Anaphylactic shock is life threatening- about 0.1% of Americans have an anaphylactic reaction to penicillin, resulting in appx 300 deaths per year.
recent studies indicate that patients with mild allergies to penicillin frequently lose their sensitivity to it over time.
the development of resistant population of pathogens can be averted in least 4 ways: 1. sufficiently high concentration of the drug can be maintained in a patient's body for a long enough time to inhibit the pathogen allowing the bodys defenses to defeat them-discounting a drug too early promotes the development of resistant strains-it is important that patients finish their entire antimicrobial prescription and resist the temptation to "save some for another day" 2. use antimicrobial agents in combination so that pathogens resistant to one drug will be killed by other drugs and vise versa, one drug sometimes enhances the effect of a second drug in a process called synergism --synergism can also result from combining an antimicrobial drug and a chemical as occurs when clavulanic acid enhances the effect of penicillin by deactivation B-lactamase -antagonistic-interfer with each other 3. to reduce the development of resistance is to limit the use of antimicrobials to necessary cases. unfortunately many antimicrobial agents are used indiscriminately, both in developed countries and in less developed regions where many agents are available without a physicians prescription -in the US 50% of prescriptions for antibacterial agents to treat sore throats and 30% of prescriptions for ear infections are inappropriate bc the diseased are viral not bacterial 4. scientists can combat resistant strains by developing new drugs in some cases by adding different side chains to the original molecule. in this way scientists develop semisynthetic second generations drugs. if resistant develops to these drugs, third generations drugs may be developed to replace them.
researchers see potential in bacteriocins-antibacterials proteins coded by bacterial strains
antibiotics are apart of what diverse group?
secondary metabolites which are typically complex organic molecules that are not essential for normal cell growth and reproduction and are produced only after an organism has already established itself in it's environment
Protease inhibitors interfere with the action of protease-an enzyme that HIV needs near the end of it's replication cycle these drugs, when used as part of a "cocktail" of drugs including reverse transcriptase inhibitors have revolutionized treatment of AIDS patients in industrialized countries
several drugs function by blocking either the replication of DNA or its transcription into RNA
Etest- involves placing a plastic strip containing a gradient of the antimicrobial agent being tested on a plate uniformly incubation, an elliptical zone of inhibitory concentration can be noted where the zone of inhibition intersects a scale printed on the strip.
similar to the MIC test is a minimum bactericidal concentration (MBC) test, through an MBC test determines the amount of drug required to kill the microbe rather than just the amount to inhibit it, as the MIC does.
prokaryotic ribosomes are 70S and composed of 30S and 50S subunits whereas eukaryotic ribosomes are 80S with 60S and 40S subunits
some antimicrobial agents drugs affect eukaryotic mitochondria, which also contain 70S ribosomes like those prokaryotes drugs may be harmful to animals and humans especially the very active cells of the liver and bone marrow.
many common antibacterial agents act by preventing the cross-linkage of NAM subunits
the most prominent among these drugs are beta-lactams(such as penicillins, cephalosporins, and carbapenems) which are antimicrobials whose functional portions are called beta-lactam rings
other compounds that can act as antimicrobials by interfering with the function of nucleic acid are nucleotide analogs or nucleoside analogs, which are molecules with structural similarities to the normal nucleotide building blocks of nucleic acids
the structures of certain nucleotide or nucleoside analogs such as the anti-AIDS drug AZT, enable them to be incorporated into the DNA or RNA of pathogens, where they distort the shapes of the nucleic acid molecules and prevent further replication, transcription, or translation.
in addition to considering the route of administration, physicians must consider how antimicrobial agents are distributed to infected tissues by the blood.
though antimicrobial drugs are ideally selectively toxic against microbes and harmless to humans, many antimicrobials in fact have toxic side effects. therapeutic index (TI) which is essentially a ratio comparing the dose of the drug that a patient can tolerate to the drug's effective dose. the higher the TI the safer the drug Clinicians refer to a drug's therapeutic range (therapeutic window) which is the range of concentrations of the drug that are effective without being excessively toxic
Streptomyces
useful antimicrobials, most notably species of soil-dwelling bacteria