Know what is the general mechanism of inhibition of penicillin, cephalosporins, vancomycin, fluoroquinolones,

sulfonamides, erythromycin, tetracycline, clindamycin.

Mechanisms of Action
- Blocking folic acid biosynthesis (static): sulfonamide, trimethoprim
-

Inhibiting cell wall biosynthesis (cidal): beta lactams e.g. penicillins, cephalosporins, carbapenams;
glycopeptides e.g. vancomycin

Inhibiting protein synthesis (aminoglycosides cidal, rest static): aminoglycosides e.g. streptomycin,
gentamicin; tetracyclines e.g. tetracycline, doxycycline; chloramphenicol; macrolides e.g. erythromycin,
azithromycin; lincosamides e.g. clindamycin; linezolid

Blocking nucleic acid metabolism (cidal): rifampin, quinolones

Act on cell membrane (cidal; toxicity): daptomcin, polymyxin

Sulfonamides
- Mechanism: inhibit folate synthesis. Para-aminobenzoic acid (PABA) antimetabolites inhibit
dihydropteroate synthase
- Clinical use: Gram+, Gram-, Nocardia, Chlamydia. Triple sulfas or SMX for simple UTI.
o This works for treating UTIs but not for something with pus, because the WBCs break down and
provide the medium for the bacteria to grow.
o Drawbacks: bacteriostatic, fails in presence of pus, acquired resistance, toxicity
- Toxicity: Hypersensitivity reactions, hemolysis if G6PD deficient, tubulointerstitial nephritis,
photosensitivity, kernicterus in infants, displace other drugs from albumin e.g. warfarin
- Mechanisms of resistance: Altered enzyme (bacterial dihydropteroate synthase), decrease uptake or
increase PABA synthesis
Trimethoprim
- Mechanism: inhibits bacterial dihydrofolate reductase
- Clinical use: Used in combination with sulfonamides TMP-SMX to cause sequential block of folate
synthesis
o Combination used for UTIs
o Shigella, Salmonella, Pneumocystis jirovecii pneumonia treatment and prophylaxis
o Toxoplasmosis prophylaxis
- Toxicity: Megaloblastic anemia, leukopenia, granulocytopenia (may alleviate with supplemental folinic
acid)
o TMP = Treats Marrow Poorly
Penicillin
- Penicillin G (IV and IM form), Penicillin V (oral form)
- Mechanism: bind penicillin-binding proteins to block transpeptidase cross-linking of peptidoglycan;
activate autolytic enzymes
- Clinical use: Mostly for Gram+ organisms (S. pneumonia, S. pyogenes, Actinomyces)
o Also used for N. meningitides, T. Pallidum
o Bacteriocidal for G+ cocci, G+ rods, G- cocci, and spirochetes
o Penicillinase sensitive
- Toxicity: Hypersensitivity reactions, hemolytic anemia.
o Rash, fever, serum sickness, angioedema, anaphylaxis
- Resistance: Penicillinase in bacteria cleaves beta-lactam ring.

Cephalosporins
- Mechanism: beta-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases;
bactericidal
- Toxicity: Hypersensitivity reactions, vitamin K deficiency, low coross-reactivity with penicillins, increase
the nephrotoxicity of aminoglycosides
Vancomycin (glycopeptide)
- Mechanism: inhibits cell wall peptidoglycan formation by binding D-ala D-ala portion of cell wall
precursors. Bactericidal. Can be used in patients with allergy to penicillin.
- Clinical Use: Gram positive only serious MDR organisms, e.g. MRSA, enterococci, C. difficile.
- Toxicity: well tolerated but has potential for Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse
flushing- red man syndrome (prevent by pretreatment with antihhistmaines and slow infusion rate)
- Resistance: Occurs in bacteria via AA modification of D-ala D-ala to D-ala D-lac.
Antibiotics that block bacterial protein synthesis
- 30S subunit
o Aminoglycosides e.g. streptomycin, gentamicin
o Tetracyclines e.g. tetracycline, doxycycline, tigecycline
- 50S subunit
o Macrolides, clindamycin, chloramphenicol, pristinamycins, linezolid
- Streptomycin: binds to 16S rRNA of 30S subunit
- Tetraycline: Tetracyclines can be given orally or IV. Good for outpatient therapy. Broad spectrum of
activity. For streptomycin, worked against TB so that was the first effective agent against TB. (?)
- Linezolid: protein synthesis inhibitor, last ditch agent in treating MRSA and other Gram+
Mechanism of protein synthesis inhibition
- Aminoglycoside, chloramphenicol, and tetracyclines interfere with binding of aminoacyl-tRNA to A
site
- Clindamycin inhibits peptidyl transferase reaction at both A and P sites
- Linezolid blocks peptide formation
- Erythromycin blocks peptide exit tunnel
- Binding sites of several overlap
Tetracycline: bacteriostatic, targets 30S A-site tRNA binding
Clindamycin, erythromycin: targets 50S translocation
Tetracyclines
- Mechanism: bind to 30S and prevent attachment of aminoacyl-tRNA, limited CNS penetration
- Clinical use: borrelia burgdorferi
- Toxicity: GI distress, discloroation of tteeth, inhibition of growth in children, photosensitivity,
contraindicated in pregnancy
- Resistance: decrease uptake or increase efflux out of bacterial cells by plasmid-ecnoded transport pumps
Erythromycin (macrolide)
- Mechanism: inhibit protein synthesis by blocking translocation; bind to the 23S rRNA of the 50S ribosoma
subunit. Bacteriostatic.
- Clinical use: atypical pneumonia, STD, Gram positive cocci
- Toxicity: GI motility, arrhythmia, acute cholestatic hepatitis, rash, eosinophilia
- Resistance: methylation of 23S rRNA-binding site prevents binding of drug
Clindamycin
- Blocks peptide transfer (translocation) at 50S ribosomal subunit. Bacteriostatic
- Clinical use: anaerobic infections, lung abscesses, oral infections, invasive Group A streptococcal infection
o Treats anaerobes above diaphragm
- Toxicity: pseudomembranous colitis (C. dificile overgrowth), fever, diarrhea

Fluoroquinolones e.g. ciprofloxacin, levofloxacin

- Mechanism: inhibit DNA gyrase (topoisomerase II) and topoisomerase IV. Bactericidal
o DNA gyrase primary in gram negatives
o Topoisomerase IV primary in Gram positives
- Clinical use: gram negative rods of UTI and GI tract e.g. Pseudomonas, Neisseria, and some gram positive
organisms
- Resistance: chromosome encoded mutation in DNA gyrase, plasmid-mediated resistance, efflux pumps
Antibiotics targeting DNA metabolism
- Rifampin
o Targets DNA dependent RNA polymerase
o Broad spectrum including tbc
o Cidal
o Ready emergence of resistance mutations in AA that prevent effectivebinding of drug
o
- Quinolones
o Target DNA gyrase and topoisomerase IV
Produces a double stranded break that it cant repair
o Broad spectrum also including tbc
o Cidal
o Resistance also a problem changes in DNA gyrase can make it less sensitive
o Good against Gram negative
o Ciprofloxacin, levofloxacin, moxifloxcin
Agents that target cell membrane
- Daptomycin cyclic lipopeptide
- Polymyxin complex (E = colistin)
o Toxic effects on kidney and nervous system
ANTIBIOTIC RESISTANCE
Methods to test susceptibility
- Disk (with known concentration of antibiotic)
- Etest (where growth stops is MIC)
- Tube dilution can measure MIC or MBC
Mechanisms of resistance
- Target alteration
- Drug modification
- Decreased accumulation, e.g. efflux pumps
- Intrinsic and acquired
o Mutation
o Altered gene expression
o Horizontal gene transfer, e,g. plasmids
Sulfonamide and Trimethoprim Resistance
- Natural or acquired chromosomal folate biosynthetic enzymes insensitive to inhibition
- Plasmid-mediated sul or dfr genes coding for inhibitor resistant replacement enzymes
o Sul: dihydropteroate synthase
o Dfr: dihydrofolate reductase
Beta-Lactam Resistance

Beta-lactamases
o Serine based and Zn-based
o ESBL: extended-spectrum beta-lactamases
TEM, CTX-M
o Carbapenamase: KPC, NDM
Altered PBPs
o Methicillin resistant S. aureus
SCCmec casettes
o Penicillin resistant S. pneumonia, Enterococcus

Vancomycin Resistance
- VRE: conversion of D-Ala D-Ala to D-Ala D-lac, reducing affinity for drug (loss of one binding site)
- VISA: thickened cell walls, decreased autolytic activity
- VRSA: acquisition vanA gene from enterococci
Aminoglycoside Modifications
- Acetyl-, nucleototidyl-, and phosphotransferases
- 16S rRNA methylase
- Ribosomal mutation: S12 protein of 30s or 16S rRNA
Quinolone Resistance
- AA substitutions to most sensitive target: DNA gyrase A for Gram negatives and topoisomerase IV for
Gram positive
- Decreased accumulation
- Plasmid mediated target block, inactivation, or efflux
Efflux
- Five types of efflux pumps: OMF, RND, MF, SMR, ABC
- Low level resistance to many agents: coresistance and resistance augmentation
Beta-lactamase inhibitors: clavulanate, sulbactam, tazobactam
Circumvent resistance mechanism: add side chains