Overview of mechanisms of bacterial resistance

Many antimicrobial agents have been either found in nature or synthesized in the past 45 years. Antibacterial agents inhibit cell-wall formation, disrupt cytoplasmic membrane function, prevent DNA synthesis, interfere with protein synthesis, and halt folate synthesis. Resistance to antibiotics is a result of three major mechanisms: prevention of the antibacterial agent from reaching its receptor site, production of altered targets, and destruction or modification of the agents. Bacterial resistance has occurred due to chromosomal changes or the presence of plasmids and transposons. Resistance to beta-lactams is the result of beta-lactamases and the production of altered penicillin-binding proteins as well as altered cell-wall permeability. Important examples of these resistance forms occur in staphylococci and pneumococci which have altered penicillin-binding proteins. A new form of target change has been the production of proteins in enterococci that inhibit the activity of glycopeptides. Beta-lactamases are present in both Gram-positive and Gram-negative species; recently, new plasmid beta-lactamases have been isolated that destroy iminomethoxy and iminocarboxy cephalosporins. Resistance to aminoglycosides is due to enzymes that acetylate, adenylate, or phosphorylate aminoglycosides that inhibit binding to ribosomes and thus cause the poor uptake of drug. Tetracycline resistance is due to plasmids which cause efflux of the agent from the cytoplasm. Macrolide and lincinoid resistance is the result of an altered 23S ribosomal component of the 50S ribosomes. Sulfonamide and trimethoprim resistance is due to production of altered synthetase and reductase enzymes essential in the synthesis of folate. Resistance to new fluoroquinolones is due both to altered DNA gyrase and to cell-wall changes that prevent entry of the compound. Although resistance has been a major problem, the production of molecularly modified compounds and beta-lactamase inhibitors and the development of newer drugs have provided agents for treating highly resistant bacteria.