There are four major mechanisms that mediate bacterial resistance to drugs.

 (1) Bacteria produce enzymes that inactivate the drug (e.g., ß-lactamases can inactivate penicillins and cephalosporins by cleaving the ß-lactam ring of the drug).

 (2) Bacteria synthesize modified targets against which the drug has a reduced effect (e.g., a mutant protein in the 30S ribosomal subunit can result in resistance to streptomycin, and a methylated 23S rRNA can result in resistance to erythromycin).

 (3) Bacteria reduce permeability to the drug such that an effective intracellular concentration of the drug is not achieved (e.g., changes in porins can reduce the amount of penicillin entering the bacterium).

 (4) Bacteria actively export drugs using a "multidrug-resistance pump" (MDR pump, or "efflux" pump). The MDR pump imports protons and, in an exchange-type reaction, exports a variety of foreign molecules including certain antibiotics, such as tetracyclines.

Most drug resistance is due to a genetic change in the organism, either a chromosomal mutation or the acquisition of a plasmid or transposon. Nongenetic changes, which are of lesser importance.

The term high-level resistance refers to resistance that cannot be overcome by increasing the dose of the antibiotic. A different antibiotic, usually from another class of drugs, is used. Resistance mediated by enzymes such as ß-lactamases often result in high-level resistance, as all the drug is destroyed. Low-level resistance refers to resistance that can be overcome by increasing the dose of the antibiotic. Resistance mediated by mutations in the gene encoding a drug target is often low level, as the altered target can still bind some of the drug but with reduced strength. To illustrate the use of these terms, strains of Neisseria gonorrhoeae that produce penicillinase cannot be treated successfully with penicillin G. They exhibit high-level resistance, and a different drug such as ceftriaxone must be used.

However, strains of N. gonorrhoeae that synthesize altered penicillin-binding proteins exhibit low-level resistance and can be treated successfully with high-dose penicillin G.