Mechanism of action of important chemotherapeutic agents ( Medical Microbiology, B.Sc Microbiology, Semester VI)
Unit 8: Antimicrobial agent and drug resistance: Mechanism of action of important chemotherapeutic agents
Chemotherapeutic agents are chemical substances used for the treatment of infectious diseases or diseases caused by the proliferation of malignant cells. These substances are prepared in the chemical laboratory or obtained from microorganisms.To be useful as a chemotherapeutic agent a substance must have selective toxicity for the parasite, which means low toxicity for host cells and high toxicity for the parasites. The degree of selective toxicity may expressed in terms of the therapeutic dose, the drug level required for clinical treatment of a particular infection, and the toxic dose, the drug level at which the agent becomes too toxic for the host.
The mechanisms of action of specific chemotherapeutic agents are important to know as such knowledge helps to explain the nature and degree of selective toxicity of individual drugs and sometimes aid in the design of new chemotherapeutic agents.
The most selective antibiotics are those that interfere with the synthesis of bacterial cell walls (e.g., penicillins, cephalosporins, vancomycin, and bacitracin).
Streptomycin, gentamicin, spectinomycin, clindamycin, chloramphenicol, tetracyclines, erythromycin, and many other antibiotics inhibit protein synthesis by binding with the prokaryotic ribosome.Because these drugs discriminate between prokaryotic and eukaryotic ribosomes, their therapeutic index is fairly high but not as favorable as that of cell wall synthesis inhibitors.Some drugs bind to the 30S (small) subunit, while others attach to the 50S (large) ribosomal subunit. Several different steps in the protein synthesis mechanism can be affected: aminoacyl-tRNA binding, peptide bond formation, mRNA reading, and translocation.
The antibacterial drugs that inhibit nucleic acid synthesis or damage cell membranes often are not as selectively toxic as other antibiotics. This is because prokaryotes and eukaryotes do not differ greatly concerning nucleic acid synthetic mechanisms or cell membrane structure. Good examples of drugs that affect nucleic acid synthesis or membrane structure are quinolones and polymyxins. Quinolones inhibit the DNA gyrase and thus interfere with DNA replication, repair, and transcription. Polymyxins act as detergents or surfactants and disrupt the bacterial plasma membrane.
Several valuable drugs act as antimetabolites: they block the functioning of metabolic pathways by competitively inhibiting the use of metabolites by key enzymes. Sulfonamides and several other drugs inhibit folic acid metabolism. Sulfonamides (e.g., sulfanilamide, sulfamethoxazole, and sulfacetamide) have a high therapeutic index because humans cannot synthesize folic acid and must obtain it in their diet.
References - Microbiology, 5th edition, Lansing M. Prescott. Chapter 35: Antimicrobial Chemotherapy
Microbiology, Fifth edition, Michael J. Pelczar, JR. Chapter 24: Antiniotics and other chemotherapeutic agents
