Friday, November 7, 2014

Take a glance on antibiotics


 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 PBP’s
(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 penetration
(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 transferase
(2) altered outer membrane (chromosomal mutations)
Macrolides ---> 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

 Alteration of Cell Membranes

Polymyxins (topical) ---> Cationic detergent-like activity (topical use)
Resistance ---> inability to penetrate outer membrane
Bacitracin (topical) ---> Disrupt cytoplasmic membranes
Resistance ---> inability to penetrate outer membrane

 Inhibition of Nucleic Acid Synthesis

 DNA Effects
Quinolones ---> Inhibit DNA gyrases or topoisomerases required for supercoiling of DNA; bind to alpha subunit
Resistance --->
(1) alteration of alpha subunit of DNA gyrase (chromosomal)
(2) decreased uptake by alteration of porins (chromosomal)
Metronidazole ---> Metabolic cytotoxic byproducts 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

https://www.youtube.com/watch?v=NGwP471sehI
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 synergism

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