Mechanisms of bacterial resistance to antibiotics.

The three fundamental mechanisms of antimicrobial resistance are (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that are antimicrobial targets, and (3) changes in membrane permeability to antibiotics. Antibiotic resistance can be either plasmid mediated or maintained on the bacterial chromosome. The most important mechanism of resistance to the penicillins and cephalosporins is antibiotic hydrolysis mediated by the bacterial enzyme beta-lactamase. The expression of chromosomal beta-lactamase can either be induced or stably depressed by exposure to beta-lactam drugs. Methods to overcome resistance to beta-lactam antibiotics include the development of new antibiotics that are stable to beta-lactamase attack and the coadministration of beta-lactamase inhibitors with beta-lactam drugs. Resistance to methicillin, which is stable to gram-positive beta-lactamase, occurs through the alteration of an antibiotic target protein, penicillin-binding protein 2. Production of antibiotic-modifying enzymes and synthesis of antibiotic-insensitive bacterial targets are the primary resistance mechanisms for the other classes of antibiotics, including trimethoprim, the sulfonamides, the aminoglycosides, chloramphenicol, and the quinolone drugs. Reduced antibiotic penetration is also a resistance mechanism for several classes of antibiotics, including the beta-lactam drugs, the aminoglycosides, chloramphenicol, and the quinolones.