Antimicrobials 1
~1 min read
Lesson 12 of 17
Notes
Antibiotic resistance arises through five broad mechanisms: restricting antibiotic access to the target (decreased permeability, increased efflux), inactivating the antibiotic (enzymatic degradation), and modifying the antibiotic target. Understanding these mechanisms is essential for rational antibiotic prescribing and stewardship.
Beta-lactamases are the most clinically important mechanism of resistance. These enzymes hydrolyse the beta-lactam ring, inactivating the antibiotic. Class A and C beta-lactamases (e.g., AmpC, ESBLs) use a serine residue to covalently bind and then hydrolyse the ring; class B beta-lactamases (metallo-beta-lactamases) are zinc-dependent and include NDM (New Delhi metallo-beta-lactamase), which has broad-spectrum activity against nearly all beta-lactams including carbapenems. Beta-lactamase inhibitors such as clavulanic acid and tazobactam irreversibly bind serine-based beta-lactamases (class A), but do not inhibit AmpC (class C) or metallo-beta-lactamases.
MRSA (methicillin-resistant Staphylococcus aureus) exemplifies target modification: the mecA gene encodes PBP2' (a modified penicillin-binding protein with low affinity for all beta-lactams), allowing peptidoglycan cross-linking to continue in the presence of any beta-lactam antibiotic. Vancomycin-resistant enterococci (VRE) achieve resistance through acquisition of an operon that changes the terminal D-alanine-D-alanine residue in peptidoglycan to D-alanine-D-lactate, preventing vancomycin binding.
Gram-negative bacteria reduce permeability by downregulating or mutating porin channels, preventing antibiotic entry into the periplasm. Efflux pumps actively expel antibiotics from the bacterial cytoplasm; some are highly specific (e.g., TetA for tetracycline), while others export multiple unrelated antibiotics (multidrug resistance efflux pumps). Critically, resistance genes are often genetically linked on plasmids or transposons, meaning selection by one antibiotic can co-select for resistance to multiple unrelated classes.