Antibiotics

Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria (antibiotics), fungi (antifungals) or viruses (antivirals).

Antibiotics can be classified according to the mechanism of action as follows:

Cell wall active agents: Beta lactam antibiotics (penicillins, cephalosporins, carbapenems and monobactams), glycopeptides (vancomycin and teicoplanin) and bacitracin (a polypeptide).

Beta lactam antibiotics bind the penicillin binding proteins or PBPs, which are building blocks of the peptidoglycan layer in the bacterial cell wall. This leads to bacterial lysis.

Glycopeptides inhibit cell wall synthesis by binding to D-alanyl D-alanine which is a component of the peptide chain.

Bacitracin inhibits cell wall synthesis by binding to and blocking a carrier molecule that is involved in the transport of polysaccharides, peptidoglycans and lipopolysaccharides to the growing bacterial cell wall.

Cell membrane active agents: Colistin (polymyxin E) and polymyxin B (both are polypeptides). They are cationic polypeptides that bind to anionic lipopolysaccharide in the outer membrane of gram negative bacteria, leading to displacement of Ca++ and Mg++ ions. This disrupts the cell membrane. Colistin also has anti-endotoxin activity as it binds to and inhibits the action of lipid A.

Inhibitors of protein synthesis: They are further grouped as inhibitors of 30S ribosomes (aminoglycosides and tetracycline) and inhibitors of 50S ribosomes (chloramphenicol, macrolides, lincosamides, streptogramins and oxazolidinones/linezolid).

Aminoglycosides cause premature termination of translation of mRNA by binding to 30S ribosome near the A site. They act synergistically with cell wall active agents like penicillins which lyse the cell wall allowing aminoglycoside to penetrate the cell and inhibit the ribosomes.

Tetracyclines prevent binding of t-RNA to the A site.

Glycylcyclines are tetracycline-like drugs which are effective in resistant Gram positive bacteria like MRSA, MRSE and VRE. Examples are tigecycline and minocycline. They both act at the 30S ribosome.

Chloramphenicol prevents binding of t RNA to the A site of the ribosome and inhibits protein synthesis.

Macrolides like erythromycin, azithromycin, clarithromycin etc, streptogramins and lincosamides result in the premature detachment of incomplete peptide chains. Streptogramins include quinupristin, dalfopristin, pristinamycin etc. Lincosamides include clindamycin.

Telithromycin is a ketolide antibiotic that not only binds to domain V of ribosomal RNA like macrolides, but also binds to domain II and inhibits protein synthesis. Telithromycin has greater bioavailability than erythromycin. Use is limited by toxicity though.

Linezolid prevents formation of the initiation complex for protein synthesis.

Inhibitors of DNA inhibition: They inhibit DNA synthesis or replication and include quinolones, sulfonamides and trimethoprim.

Fluoroquinolones inhibit the enzyme DNA gyrase a topoisomerase IV, the enzyme that introduces negative supercoils in DNA.

Sulfonamides and trimethoprim inhibit different steps in the folate synthesis. Sulfonamides are competitive inhibitors of dihydropteroate synthase, while trimethoprim inhibits dihydrofolate reductase.

Rifampin or rifampicin: It inhibits bacterial transcription by inhibiting the enzyme RNA polymerase. Bacteria acquire resistance to rifampin by changing the structure of the beta subunit of RNA polymerase (rpoB gene mutations). It is a bactericidal drug and is effective against Mycobacterium tuberculosis, staphylococci, brucella, chlamydia, rickettsia and bacteroides.