Basic Mechanisms of Antibiotic Action and Resistance
Five Basic Mechanisms of Antibiotic
Action against Bacterial Cells:
1. Inhibition of Cell Wall
Synthesis (most common mechanism)
2. Inhibition of Protein
Synthesis (Translation) (second largest class)
3. Alteration of Cell Membranes
4. Inhibition of Nucleic Acid Synthesis
5. Antimetabolite Activity
Inhibition of Cell Wall Synthesis
Beta-Lactams ---> Inhibition of peptidoglycan synthesis (bactericidal)
Resistance --->
(1) fails to cross membrane (gram negatives)
(2) fails to bind to altered PBPs
(3) hydrolysis by beta-lactamases
Vancomycin ---> Disrupts peptidoglycan cross- linkage
Resistance --->
(1) fails to cross gram negative outer membrane (too
large)
(2) some intrinsically resistant (pentapeptide terminus)
Bacitracin ---> Disrupts movement of peptidoglycan precursors (topical use)
Resistance ---> fails to penetrate into cell
Antimycobacterial agents ---> Disrupt mycolic acid or arabinoglycan synthesis (bactericidal)
Resistance --->
(1) reduced uptake
(2) alteration of target sites
Inhibition of Protein
Synthesis (Translation)
30S Ribosome site
Aminoglycosides
---> Irreversibly bind 30S ribosomal proteins (bactericidal)
Resistance --->
(1) mutation of ribosomal binding site
(2) decreased
uptake
(3) enzymatic modification of antibiotic
Tetracyclines ---> Block tRNA binding to 30S ribosome-mRNA complex (b-static)
Resistance --->
(1) decreased penetrate
(2) active efflux of antibiotic out of cell
(3) protection of 30S ribosome
50S Ribosome site
Chloramphenicol
---> Binds peptidyl transferase component of 50S ribosome, blocking peptide
elongation (bacteriostatic)
Resistance --->
(1) plasmid-encoded chloramphenicol transferaseMacrolides ---> Reversibly bind 50S ribosome, block peptide elongation (b- static)
Resistance --->
(1) methylation of 23S ribosomal RNA subunit
(2) enzymatic cleavage (erythromycin esterase)
(3) active efflux
Clindamycin ---> Binds 50S ribosome, blocks peptide elongation; Inhibits peptidyl transferase by interfering with binding
of amino acid-acyl-tRNA complex
Resistance ---> methylation of 23S ribosomal RNA subunit
Inhibition of Nucleic Acid Synthesis
DNA Effects
Quinolones ---> Inhibit DNA gyrases or topoisomerases required for supercoiling of DNA; bind to the alpha subunit
Resistance --->
(1) alteration of alpha subunit of DNA gyrase
(chromosomal)
(2) decreased uptake by alteration of porins
(chromosomal)
Metronidazole ---> Metabolic cytotoxic by-products disrupt DNA
Resistance --->
(1) decreased
uptake
(2) elimination of toxic compounds before they
interact
RNA Effects (Transcription)
Rifampin ---> Binds to DNA-dependent RNA polymerase inhibiting initiation & Rifabutin of RNA synthesis
Resistance --->
(1) altered of beta subunit of RNA polymerase
(chromosomal)
(2) intrinsic resistance in gram negatives (decreased uptake)
Bacitracin (topical) ---> Inhibits RNA transcription
Resistance ---> inability to penetrate outer membrane
Antimetabolite Activity
Sulfonamides & Dapsone ---> Compete with p-aminobenzoic acid (PABA) preventing synthesis of folic acid
Resistance ---> permeability barriers (e.g., Pseudomonas)
Trimethoprim ---> Inhibit dihydrofolate reductase preventing synthesis of folic acid
Resistance --->
(1) decreased affinity of dihydrofolate reductase
(2) intrinsic resistance if use exogenous thymidine Trimethoprim-Sulfamethoxazole
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