Microorganisms may develop resistance to various drugs by:

Decreased affinity for the target e.g. pneumococci and staphylococci may develop altered penicillin binding proteins. Development of alternative metabolic pathway e.g. sulfonamide resistant organisms start utilizing preformed folic acid in place of synthesizing it from PABA. Elaboration of the enzymes which inactivate the drug e.g. β-lactamases (penicillins and cephalosporins), chloramphenicol acetyl transferase (chloramphenicol) and aminoglycoside inactivating enzymes (aminoglycosides). Decreased drug permeability due to the loss of specific channels e.g. aminoglycosides and tetracyclines attain much lower drug concentration in the resistant organisms than in the sensitive organisms. Development of efflux pumps (tetracyclines, erythromycin and fluoroquinolones) results in active extrusion of the drug from the resistant microorganisms.