Antimicrobials

Drug class: Sulfonimides Resistant mechanisms?

-Alterations in dihydropterate synthase

Drug class: Vancomycin Resistant mechanisms?

-Amino acid modification of peptidoglycan precursors to D-Ala-D-Ala to D-D-Lac (van genes in Enterococci and S. aureus) -Efflux pumps

Drug class: Cephalosporins Resistant mechanisms?

-Beta-lactamases (cephalosporinase) -Reduced affinity for PBPs

Terbinafine What are the Adverse reactions?

-GI upsets -headache -dizziness -rash -taste alteration

Azoles: Ketoconazole Fluconazole Voriconazole What are the Adverse reactions?

-GI upsets and rash -Voriconazole causes visual disturbances -Ketoconazole inhibits hepatic P450 enzymes

Echinocandins: Caspofungin What are the Adverse reactions?

-Hepatotoxicity -gastrointestinal distress -flushing from histamine release

Drug class: Tetracycline Resistant mechanisms?

-Inactivation -↓ porins

Drug class: Chloramphenicol Resistant mechanisms?

-Inactivation by acetylation -Ribosomal methylation

Drug class: Carbapenems Resistant mechanisms?

-Inactivation by carbapenemases -Reduction in porin number -- Enterobacteriaceae

Drug class: Fluroquinolones Resistant mechanisms?

-Modifications in DNA gyrase or topoisomerase -Efflux pumps

Polyenes: Amphotericin B Nystatin What are the Adverse reactions?

-Nephrotoxicity is dose limiting Amphotericin B: -Infusion reactions (chills, fever, muscle spasms, hypotension) -kidney damage Nystatin: -GI disturbances -photosensitivity

Transpeptidases: Targets of blactams and Vancomycin

-Penicillin and other βlactams bind to the transpeptidase (PBP), preventing it from carrying out its function. -Vancomycin binds directly to the amino acids, preventing the binding of transpeptidase. Vancomycin resistance: -D-alanine-D-alanine at the end of the peptidoglycan cell changed to D-alanine-D-lactate ; reduced binding.

Zooming into the Cell Wall: Peptidoglycan Structure

-Peptidoglycan is like a mesh. -The glycan portion makes up the backbone. -It made of a linear polymer of alternating NAM and NAG. -Short strings of amino acids (pentapeptides) cross-link the glycan strands. -Transpeptidases (Penicillin-binding proteins, PBPs) catalyze the cross-liking of the amino acid side chains

Drug class: Macrolides Resistant mechanisms?

-Ribosomal mutation, methylation

Drug class: Aminoglycoside Resistant mechanisms?

-Ribosomal mutations -Ribosomal subunit methylation -Inactivation by acetylation, phosphorylation, or adenylation

Vancomycin resistance

-Vancomycin requires that D-alanine-D-alanine be at the end of the peptidoglycan cell wall precursors of gram-positive bacteria. -Resistant strains in Enterococcus faecium and Enterococcus faecalis encode a protein that synthesizes D-alanine-D-lactate instead of D-alanine-D-alanine; reduced binding.

Mechanisms of Antimicrobial Resistance: Intrinsic Resistance

A trait within a bacterial species that renders it resistant to the antimicrobial • E.g., Mycoplasma are intrinsically resistant to all drugs that the target cell wall - they don't have a cell wall Common mechanism: -Reduced permeability of the outer membrane (Gram-negative bacteria) or natural activity of efflux pumps

An 8-year-old male presents with pharyngitis and fever for the last 2 days. Microbiology testing reveals small, translucent, beta-hemolytic colonies sensitive to bacitracin. The patient's history includes an allergic reaction to amoxicillin. Which of the following drugs is most likely appropriate for this patient? A. Azithromycin B. Cefaclor C. Penicillin G D. Penicillin V E. Polymyxin B

A. Azithromycin Alternative to amoxicillin; short-course antibiotic treatment

Vancomycin

A. Normally, peptidoglycan precursors composed of two sugars and a fiveamino-acid peptide are exported from the bacterial cell and added to a growing peptidoglycan chain as the cell wall enlarges. B. Vancomycin inhibits peptidoglycan chain elongation by binding to the D-ala-D-ala terminal peptides on the precursor. C. The basis of vancomycin resistance in Enterococcus is the production of precursors with D-lactate in the position of the terminal D-ala. This blocks the binding of vancomycin and allows the precursor to be incorporated.

Mechanisms of Acquired Antimicrobial Resistance

Acquisition of genetic material such as plasmids that renders the bacterium resistant

Azoles: Ketoconazole Fluconazole Voriconazole What are the Clinical uses?

Alternative drugs in candidemia and infections caused by Aspergillus, Blastomyces, Cryptococcus, and Histoplasma

Hospital-acquired pneumonia -Commonly Used Antibiotic Combinations

Ampicillin/sulbactam or antipseudomonal penicillin plus aminoglycoside Common: Alternative to monotherapy with respiratory fluoroquinolones or antipseudomonal penicillin or third generation cephalosporin

A 57-year-old transient man comes to the emergency department with fever and difficulty breathing. He is diagnosed with pneumonia and after blood and sputum cultures are obtained, he is started on azithromycin monotherapy. The next day his cultures show that the pathogen is resistant to the antibiotic, and he is switched to a fluoroquinolone. Which of the following is the likely mechanism of resistance to azithromycin? A. Modification of peptidoglycan precursors B. Upregulation of penicillinase expression C. Alterations in dihydropteroate synthase D. Methylation of ribosome E. Activation of efflux pump

Answer is D (Macrolides) All the other choices: A. Vancomycin; B. penicillins; C. sulfonamides; E. Vancomycin, Fluoroquinolones

Antimicrobial therapy

Antimetabolites: if you don't have folic acid you don't have DNA. -Sulfonamides can treat g+ and g-; Trimethoprim g+ and g- = TMP/SMS; combined bactericidal. Use: Diarrhea, UTI, Pneumonia, Sinus Infection; effective against MRSA; Pneumocystis jirovecii.

Antibiotic Action and Resistance

As a general rule, agents that inhibit cell wall synthesis are bactericidal (except ethambutol), while those that inhibit protein synthesis are bacteriostatic (except rifamycins, and aminoglycosides).

A 67-year-old woman with congenital bicuspid aortic valve is admitted to the hospital because of a 2-day history of fever and chills. Current medication is lisinopril. Temperature is 38.0°C (100.4°F), pulse is 90/min, respirations are 20/min, and blood pressure is 110/70 mm Hg. Blood culture grows viridans streptococci susceptible to penicillin. In addition to penicillin, an antibiotic synergistic to penicillin is administered that may help shorten the duration of this patient's drug treatment. Which of the following is the most likely mechanism of action of this additional antibiotic on bacteria? A. Binding to DNA-dependent RNA polymerase B. Binding to 30S ribosomal protein C. Competition with p-aminobenzoic acid D. Inhibition of dihydrofolate reductase E. Inhibition of DNA gyrase

B. Binding to 30S ribosomal protein Add an aminoglycoside - MOA: binding to the aminoacyl site of the 30s ribosome (gentamycin; tobramycin;...) IM or IV.

A 47-year-old woman is admitted to the hospital for treatment of pneumococcal pneumonia. Treatment with gentamicin and penicillin is initiated. Within 10 minutes of the administration of antimicrobial therapy, her respirations increase to 30/min, and blood pressure decreases to 80/40 mm Hg. Epinephrine, antihistamine, and corticosteroid therapy is started. Her condition improves slowly during the next 2 hours. Her antimicrobial therapy is changed to gentamicin only, and her condition continues to improve. Administration of which of the following types of drugs is most likely to cause a similar adverse reaction in this patient? A. Macrolides B. Cephalosporins C. Fluoroquinolones D. Tetracyclines E. Sulfonamides

B. Cephalosporins Anaphylaxis is a side effect of Cephalosporins, a cell wall inhibitor.

Christine Tsang is a 38-year old woman who was severely injured in a motor vehicle accident. She underwent emergency surgery yesterday and remains on a ventilator in the ICU. This morning she developed a high fever. Because this is considered a healthcare acquired infection, she is presumed be infected with a multidrug resistant organism (MDRO) that is either Gram-negative or Gram-positive. How will you cover both the possibility of a Gram positive and Gram-negative MDRO until lab results are available?

Because healthcare acquired, you presume this is multiply drug resistant organism(s) until proven otherwise, so you need to use drugs to which there is less resistance (so-called "big guns") 1. Gram-negative - extended spectrum b lactam (with a b lactamase inhibitor) 2. MRSA - Vancomycin

Endocarditis by staphylococci, enterococci, or relatively resistant streptococci (Infection-Clinical Setting) -Commonly Used Antibiotic Combinations

Beta-lactam or vancomycin plus an aminoglycoside Comment: Rifampin added in cases of prosthetic valve endocarditis

Community-acquired pneumonia -Commonly Used Antibiotic Combinations

Beta-lactam plus a macrolide Comment: Alternative to monotherapy with respiratory fluoroquinolones

Intra-abdominal infections -Commonly Used Antibiotic Combinations

Beta-lactams or ciprofloxacin plus metronidazole

Polyenes: Amphotericin B Nystatin What is the Mechanism of action?

Binds to ergosterol in fungal cell membranes, forming leaky pores

Flucytosine What are the Adverse reactions?

Bone marrow suppression

Tommy Miller is a 2-year old who presents with an earache. His left tympanic membrane is bulging and his temperature is 38o 3C (101o F). You suspect this may be bacterial; several Gram-negative bacteria extracellular (nontypeable Haemophilus influenza and Moraxella catarrahalis) and Gram-positive bacteria (Streptococcus pneumoniae) can cause earaches. How to pick a class:

Both Gram-positive and Gram-negative bacteria are possible, community acquired, extracellular bacteria - need a broader spectrum b lactam such as an amino-penicillin (Augmentin = amoxicillin+clavulanate OR 3rd generation cephalosporin; go with latter if recurrent infection)

A 62-year-old female comes to the office because her surgical wound has been bleeding for 1 hour. She underwent unilateral mastectomy 2 weeks ago for breast adenocarcinoma. She explains that she sat up in bed too quickly and her mastectomy wound split apart. Medications include doxorubicin, acetaminophen, vitamin K, ondansetron, and dicloxacillin. Physical exam shows complete dehiscence of the mastectomy wound. The offending medication included in her therapeutic regimen belongs most likely to which of the following drug classes? A. Fluoroquinolones B. Penicillins C. Anthracyclines D. Macrolides E. Carbapenems

C. Anthracyclines Antitumor antibiotics such as doxorubicin prevent wound healing due to inhibition of cell growth

A 23-year-old woman complained to her physician of urinary frequency, pain upon urination, and a mucopurulent vaginal discharge. One year earlier, the patient had undergone an anaphylactic reaction to penicillin. A Gram stain of the exudate revealed gram-negative cocci. Which of the following drugs is most likely to induce a reaction similar to penicillin in this patient? A. Levofloxacin B. Ciprofloxacin C. Ceftriaxone D. Trimethoprim E. Sulfamethoxazole

C. Ceftriaxone Cephalosporin hypersensitivity: Ceftriaxone

A 73-year-old man diagnosed with pneumonia due to Pseudomonas aeruginosa was started on piperacillin; 2 days later, there was no improvement. The physician suspected that the infective organism is resistant to the drug. Which of the following is most likely the mechanism of bacterial resistance to this antibiotic? A. Increased affinity of penicillin-binding protein to the drug B. Inhibition of drug binding to the 50S subunit C. Decreased permeability of the bacterial cell membrane to the drug D. Inhibition of the efflux pump of the bacteria cell membrane E. Decreased production of the enzyme beta-lactamase

C. Decreased permeability of the bacterial cell membrane to the drug When grown on the supportive nutrient agar this bacterium produces a pigment called pyocyanin (structure shown above)

A 68-year-old man diagnosed with streptococcal pneumonia started treatment with a third-generation cephalosporin. Which of the following steps in the turnover of the bacterial cell wall is specifically inhibited by this antibiotic? A. Autolysin-mediated breakage of peptidoglycan chains B. Elongation of linear amino sugar chains C. Inhibition of transpeptidase D. Synthesis of N-acetylmuramic acid E. Formation of a glycosidic bond between two sugar units

C. Inhibition of transpeptidase MOA: Peptidoglycan cross-linking

Polyenes: Amphotericin B Nystatin What are the Clinical uses?

Candidemia and infections caused by Amphotericin B: -Aspergillus -Blastomyces -Cryptococcus -Histoplasma Nystatin: -Candida

Skin and soft tissue infections (especially diabetic foot) -Commonly Used Antibiotic Combinations

Ciprofloxacin plus metronidazole or clindamycin Common: Alternatively cephalosporin plus metronidazole or clindamycin

A 67-year-old man decides to mow his lawn mid-day on a sunny and hot Saturday. He does not wear his hat inside assuming that it will not take a long time. It takes him much longer than he expected. When he walks into the house, he notifies a symmetrically red rash affecting on his face and neck. He is currently on antibiotic treatment for bacterial enteritis. wife gasps when she sees his face (see below). Recent use of which of the following medications would most likely cause this to happen? A. Meropenem B. Cefaclor C. Erythromycin D. Ciprofloxacin E. Clindamycin

D. Ciprofloxacin

A 69-year-old man recently diagnosed with a Proteus mirabilis infection started treatment with a daily intramuscular injection of gentamicin. Which of the following pairs of properties best explains why the drug is usually administered once daily despite its short half-life of gentamicin about 2 hours? A. Time-dependent killing and bactericidal effect B. Extensive plasma protein binding and bactericidal effect C. Concentration-dependent killing and bacteriostatic effect D. Concentration-dependent killing and long post-antibiotic effect E. Time-dependent killing and long post-antibiotic effect

D. Concentration-dependent killing and long post-antibiotic effect

In the treatment of a urinary tract infection in a patient known to have a deficiency of glucose-6-phosphate dehydrogenase, it would not be advisable to prescribe which of the following? A. Ciprofloxacin B. Levofloxacin C. Ceftriaxone D. Sulfamethoxazole E. Cephalexin

D. Sulfamethoxazole Sulfamethoxazole contraindicated when breastfeeding a G6PD deficiency child; UpToDate says "probably safe"

A 63-year-old male present to the emergency department due to fever, chills and confusion. Has is diabetic with a non-healing right foot ulcer. His temperature is 38.3 C (101 F), respiration rate is 23/min. Physical exam shows erythema surrounding his right foot ulcer with foul-smelling pus. Blood cultures were obtained, and treatment is started with ampicillin. The following day, blood cultures grow betalactamase producing bacteria sensitive to penicillinase-resistant antibacterial drugs. Which of the following would be an appropriate intervention? A. Continue treatment with ampicillin B. Switch to amoxicillin C. Switch to penicillin G D. Switch to oxacillin E. Switch to penicillin V

D. Switch to oxacillin Ampicillin is not penicillinase-resistant

A 49-year-old woman recently diagnosed with urinary tract infection started treatment with combined trimethoprim-sulfamethoxazole. Which of the following best explains the main reason for combining these two drugs? A. To delay the metabolism of both drugs B. To decrease the risk of allergic reactions C. To increase the bioavailability of trimethoprim D. To achieve a bactericidal effect that is unlikely with either drug given alone E. To achieve a longer duration of action of sulfamethoxazole

D. To achieve a bactericidal effect that is unlikely with either drug given alone

A 65-year-old woman was admitted to the emergency department with altered consciousness, fever, nausea, and vomiting. Vital signs on admission were blood pressure 90/50 mm Hg, pulse 115 bpm, respirations 20/min, temperature 103.6°F (39.8°C). Physical examination showed a patient in obvious distress with a stiff neck and positive Brudzinski sign. Following further evaluation, a diagnosis of meningitis was made. Empiric intravenous treatment was started with ampicillin, ceftriaxone, and vancomycin. Which of the following best explains the mechanism of action common to all the given drugs? A. Misreading of messenger RNA template code B. Inhibition of tetrahydrofolate synthesis C. Inhibition of RNA polymerization D. Blockade of peptidyl-transfer RNA translocation E. Inhibition of peptidoglycan synthesis

E. Inhibition of peptidoglycan synthesis

A 15-year-old male comes to the emergency room due to painful skin sores under the right arm and fever. On-site, body temperature is 38.4 C (101.1 F). Physical examination shows boils containing pus (fig below). Empiric treatment is started with nafcillin. Two days later, sensitivity testing of pus demonstrates the presence of MRSA with little response to nafcillin. The patient is switched to vancomycin. Which of the following is the likely mechanism of resistance resulting in poor sensitivity to nafcillin? A. Active efflux of nafcillin B. DNA gyrase mutation C. Ribosome alteration D. Enzymatic degradation E. Reduced interaction with binding proteins

E. Reduced interaction with binding proteins

Enterococcal bacteremia (Infection-Clinical Setting) -Commonly Used Antibiotic Combinations

Gentamicin plus a beta-lactam or vancomycin

Rashid Jones is a 22-year old man who went camping with his friends in upstate NY last weekend. He now presents with a "bulls eye" rash and flu-like symptoms. You suspect he may have the initial stage of Lyme disease, caused by the transfer of the bacterium Borrelia burgdorferi when an infected deer tick (Ixodes scapularis) takes a blood meal. How to pick a class:

Gram-negative, arthropod-borne - Tetracycline class (doxycycline)

Winston Moyer is a 72-year old man who presents with high fever, nonproductive cough, and diarrhea. He lives in a building in the Bronx where another elderly person was recently diagnosed with Legionella pneumophila. L. pneumophila is an intracellular Gram-negative bacterium. How to pick a class:

Gram-negative, community acquired, intracellular bacteria - Macrolide

Azoles: Ketoconazole Fluconazole Voriconazole What is the Mechanism of action?

Inhibit fungal α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol.

Echinocandins: Caspofungin What is the Mechanism of action?

Inhibit β-glucan synthase decreasing fungal cell wall synthesis

Terbinafine What is the Mechanism of action?

Inhibits squalene epoxidase preventing the production of ergosterol. -Squalene accumulation is also toxic to fungi

Mechanism of MRSA

MRSA: mecA gene encodes a low-affinity bacterial transpeptidase (PBP2a)

Terbinafine What are the Clinical uses?

Mucocutaneous fungal infections due to accumulation in keratin

Drug class: Penicillins Resistant mechanisms?

Penicillin G and V: resistant mechanisms~Beta-lactamases -Mutations in penicillin-binding proteins (PBPs) Penicillin-sensitive penicillins: -Beta-lactamase (penicillinase) Penicillin-resistant penicillins: -MRSA has altered PBPs (PBP2a in acquisition of mecA gene)

The Cell Wall: Peptidoglycan Structure

Peptidoglycan is like a mesh. -The glycan portion makes up the backbone. It made of a linear polymer of alternating NAM and NAG. -Short strings of amino acids (pentapeptides) cross-link the glycan strands. -Transpeptidases (Penicillin-binding proteins, PBPs) catalyze the cross-liking of the amino acid side chains

Plasma membrane

Please don't get cell wall and plasma membrane mixed up - totally different things. Peptidoglycan = Murein. Long strings of amino-polysaccharides.

Drug class: Linezolid Resistant mechanisms?

Ribosomal methylation

Tuberculosis (Infection-Clinical Setting) -Commonly Used Antibiotic Combinations

Rifampin plus isoniazid plus ethambutol plus pyrazinamide Comment: Various combinations are used as second-line therapy in infection by resistant mycobacteria

Flucytosine What are the Clinical uses?

Synergistic with amphotericin B in Candida and cryptococcal infections

Brucella infections (Infection-Clinical Setting) -Commonly Used Antibiotic Combinations

Tetracycline plus streptomycin or rifampin plus doxycycline Comment: Combinations of fluoroquinolones and rifampin have also been used

Flucytosine What is the Mechanism of action?

The active metabolite 5-fluorouracil inhibits DNA and RNA polymerases

A 22-year-old female presents to the emergency department with a 3-day history of fever, chills, malaise, and shortness of breath. She is an intravenous heroin user. Physical examination reveals fever (39.0 degree C), blood pressure 105/58, respiratory rate of 26, blood oxygen saturation of 92%. Cardiac auscultation reveals a systolic ejection murmur; subsequent echocardiography reveals vegetations on the aortic valve. Blood cultures are positive for S. aureus; susceptibility testing reveals D-lactate rather than D-ala as a terminal amino acid in the pentapeptide peptidoglycan cell wall precursor. This amino acid substitution will likely reduce the bacteria's susceptibility to which antibiotic?

The biochemical mechanism of action of vancomycin is based on the high affinity of this antibiotic for the D-alanyl-D-alanine (D-ala-D-ala) residue, a ubiquitous component of the bacterial cell wall precursor Lipid II. -The mechanism of resistance identified in the Tn1546-based antibiotic resistance was shown to involve alteration of this dipeptide residue from D-ala-D-ala to D-alanyl-D-lactate (D-ala-D-lac), a dipeptide with substantially lower affinity for the antibiotic

Meningitis -Commonly Used Antibiotic Combinations

Third generation cephalosporin plus vancomycin Common: Ampicillin added to therapy in patients >50 y old at risk for infection withListeria monocytogenes

How to pick an antibiotic class

This pediatric patient has strep throat, caused by the Gram-positive, extracellular bacterium Streptococcus pyogenes, aka group A streptococcus (GAS) -Gram-positive, community acquired (so less likely to be drug resistant), extracellular bacteria - b-lactam or b-lactam with a b-lactamase inhibitor (e.g. Augmentin = amoxicillin + clavulanate) -Since he is allergic, give an alternative antibiotic, such as Cephalosporins; azithromycin;

Echinocandins: Caspofungin What are the Clinical uses?

Treatment of candidemia, aspergillosis

A researcher works with a drug that contains a beta-lactam ring in the molecular structure and has a similar mechanism of action such as penicillin, carbapenems monobactams, and cephalosporins. Which of the following is the correct mechanism of action? a) Inhibition of cell wall synthesis by blocking peptidoglycan crosslinking b) Binding to 30S subunit of the bacterial ribosome and inhibiting protein synthesis c) Inhibition of bacterial folic acid synthesis (antimetabolite) d) Binding to the bacterial cell membrane and causes rapid depolarization e) Inhibiting the synthesis of ergosterol, a component of the fungal cell membrane

a) Inhibition of cell wall synthesis by blocking peptidoglycan crosslinking

A researcher investigates the nephrotoxicity of drugs such as gentamicin, amikacin and tobramycin. Which of the following is the correct mechanism of action? a) Inhibition of cell wall synthesis by blocking peptidoglycan crosslinking b) Binding to 30S subunit of the bacterial ribosome and inhibiting protein synthesis c) Inhibition of bacterial folic acid synthesis (antimetabolite) d) Binding to the bacterial cell membrane and causes rapid depolarization e) Inhibiting the synthesis of ergosterol, a component of the fungal cell membrane

b) Binding to 30S subunit of the bacterial ribosome and inhibiting protein synthesis

A researcher investigates tendinitis as an adverse effect of quinolones. Which of the following is the correct mechanism of action? a) Inhibition of cell wall synthesis by blocking peptidoglycan crosslinking b) Inhibition of DNA replication and transcription c) Binding to the bacterial cell membrane and causes rapid depolarization d) Inhibiting the synthesis of ergosterol, a component of the fungal cell membrane e) Inhibition of bacterial folic acid synthesis (antimetabolite)

b) Inhibition of DNA replication and transcription

Alcohol should not be consumed by patients being treated with a certain antimicrobial agent as it can cause a disulfiram reaction. Which antimicrobial agent is this most likely to be? a) Erythromycin b) Metronidazole c) Gentamicin d) Cefazolin e) Amoxicillin

b) Metronidazole

A researcher investigates the lowest concentration of an antimicrobial that inhibits the growth of a specific microorganism isolate. Which of the following antibiotics exhibit the lowest MICs? It might be hard to determine, and more than one answer is possible. a) Penicillin b) Erythromycin c) Clindamycin d) Azithromycin e) Amoxicillin f) Doxycycline

d) Azithromycin f) Doxycycline

A researcher investigates diffuse flushing after infusion of a drug administered for infections with gram+ microbes in the hospital setting. Which of the following is the correct mechanism of action? a) Inhibition of cell wall synthesis by blocking peptidoglycan crosslinking b) Inhibition of DNA replication and transcription c) Binding to the bacterial cell membrane and causes rapid depolarization d) Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminal of the growing peptide chain e) Inhibition of bacterial folic acid synthesis (antimetabolite)

d) Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminal of the growing peptide chain

Which of the following antimicrobials is ototoxic and nephrotoxic? a) Sulfamethoxazole b) Penicillin G c) Ceftriaxone d) Ciprofloxacin e) Gentamicin

e) Gentamicin

b-lactamases

• Most common way bacteria become resistant to b lactam antibiotics is through acquisition of genes expressing b-lactamases • Enzymes produced by bacteria that break the b-lactam ring and inactivate members of the b-lactam group • Each b-lactamase is a distinct enzyme which targets specific substrates ( the drugs) • Key example: S. aureus penicillinase is active against penicillin and ampicillin, but not methicillin or cephalosporins • Some β-lactamases are bound by the β-lactamase inhibitor clavulanic acid, while others are not • Usually occurs via acquisition of plasmids

Beta-lactam antibiotics

•Definition: a group of antibiotics that contains beta-lactam ring in their molecular structure and includes penicillins, carbapenems, monobactams, and cephalosporins •Mechanism of action • Inhibit cell wall synthesis by blocking peptidoglycan crosslinking• β-lactam mimics the D-ala-D-ala structure of bacterial peptidoglycan residue. • β-lactam irreversibly binds to penicillin-binding proteins (PBPs) which act as transpeptidases → stalled crosslinking of peptidoglycan in cell wall (β-lactam cannot be cleaved) → inability to synthesize new cell wall during replication → bacterial death (bactericidal effect)