[Mechanisms of action of and resistance to rifampicin and isoniazid in Mycobacterium tuberculosis: new information on old friends].
Human tuberculosis is still one of the most frequent causes of death worldwide. Despite the implementation of therapeutic regimes combining four drugs, the rise of resistant and multidrug-resistant Mycobacterium tuberculosis strains has compromised their efficacy. Two of the most effective anti-tubercular drugs in use, rifampicin and isoniazid, have been closely studied due to their therapeutic importance. These studies have led to the identification of the genes involved in resistance mechanisms and of those encoding the molecular targets for these drugs. Rifampicin is an inhibitor of the beta-subunit of the RNA polymerase of prokaryotes, including M. tuberculosis. Resistance to rifampicin is mediated by mutations clustered in a small region of the rpoB gene. A fraction of resistant strains showed no mutations in rpoB, suggesting that other mechanisms of resistance, possibly efflux pumps, may exist. Isoniazid is a pro-drug activated by KatG, a catalase-peroxidase. Mutations in katG, the most commonly found in M. tuberculosis clinical isolates, give high levels of resistance. In spite of this, the molecular target for isoniazid is InhA, an enoyl-ACP-reductase involved in the biosynthesis of mycolic acids. Other mutations causing resistance to isoniazid have been mapped to ndh, a gene encoding the NADH dehydrogenase.
De La Iglesia
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Catedra de Microbiología, Virología y Parasitología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe 3100 2000 Rosario, Argentina.
Morbidoni
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D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D002374:Catalase; D012321:DNA-Directed RNA Polymerases; D024881:Drug Resistance, Bacterial / Q000235:genetics; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D007538:Isoniazid / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D010088:Oxidoreductases; D012293:Rifampin / Q000494:pharmacology*
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D001426:Bacterial Proteins; C505805:rpoB protein, Mycobacterium tuberculosis; D010088:Oxidoreductases; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); C085257:InhA protein, Mycobacterium; D012321:DNA-Directed RNA Polymerases; D007538:Isoniazid; D012293:Rifampin