Antimicrobial Resistance Mechanisms

Antimicrobial resistance occurs when bacteria develop mechanisms to survive exposure to antibiotics that would normally kill or inhibit them. Four major resistance mechanisms exist: (1) Enzymatic inactivation/modification: bacteria produce enzymes that destroy or modify the antibiotic. Beta-lactamases hydrolyze the beta-lactam ring (penicillins, cephalosporins); extended-spectrum beta-lactamases (ESBLs) in gram-negatives confer resistance to third-generation cephalosporins; carbapenemases (KPC, NDM, OXA) in CRE destroy carbapenems — the 'last resort' beta-lactams. Aminoglycoside-modifying enzymes acetylate, adenylate, or phosphorylate the drug. (2) Target modification: mutations alter the antibiotic's binding site. Altered penicillin-binding proteins (PBPs) cause MRSA (mecA gene encoding PBP2a); ribosomal methylation causes macrolide resistance (erm genes); DNA gyrase mutations cause fluoroquinolone resistance; vanA gene cluster in VRE alters the D-Ala-D-Ala target to D-Ala-D-Lac, preventing vancomycin binding. (3) Decreased permeability: loss of outer membrane porins (OmpF, OmpK) in gram-negatives prevents drug entry. (4) Efflux pumps: active transport of antibiotics out of the cell before they reach their target (tetracycline efflux pumps, multidrug efflux in Pseudomonas). Resistance genes are transmitted vertically (chromosomal mutation passed to offspring) or horizontally (conjugation via plasmids, transduction via bacteriophages, transformation via free DNA...