Two resistance strategies act at the point of contact between drug and target. Enzymatic inactivation uses a bacterial enzyme to chemically modify or cleave the antibiotic so it can no longer bind. Beta-lactamases hydrolyze the beta-lactam ring, the four-membered amide ring that gives penicillins and cephalosporins their reactive shape; once the ring opens, the drug cannot acylate its target penicillin-binding proteins (PBPs). Aminoglycoside-modifying enzymes instead attach acetyl, phosphoryl, or adenyl groups to the drug, and the bulky modification blocks binding to the 30S ribosomal subunit. In both cases the drug is consumed or altered before it reaches its target, so the target itself stays unchanged.
Target modification takes the opposite approach: the drug remains intact and active, but its binding site is altered. Methicillin-resistant Staphylococcus aureus (MRSA) carries the gene mecA, which encodes PBP2a, a PBP with low affinity for nearly all beta-lactams; the transpeptidation reaction that cross-links peptidoglycan still proceeds, but the drug can no longer inhibit it. Ribosomal methylation by Erm methyltransferases adds methyl groups to the 23S rRNA at the macrolide binding site, so macrolides, lincosamides, and streptogramin B can no longer block the exit tunnel. Mutations in the genes encoding DNA gyrase or topoisomerase IV change the fluoroquinolone binding pocket, so the drug cannot trap the enzyme-DNA complex. The unifying logic is that the essential function survives while the drug's grip is lost.