De La Iglesia A I, Morbidoni H R
Catedra de Microbiología, Virología y Parasitología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe 3100 2000 Rosario, Argentina.
Rev Argent Microbiol. 2006 Apr-Jun;38(2):97-109.
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.
人类结核病仍然是全球最常见的死亡原因之一。尽管实施了四种药物联合治疗方案，但耐药和耐多药结核分枝杆菌菌株的增加损害了这些方案的疗效。利福平和异烟肼是目前使用的两种最有效的抗结核药物，由于其治疗重要性，它们已得到深入研究。这些研究已确定了参与耐药机制的基因以及编码这些药物分子靶点的基因。利福平是包括结核分枝杆菌在内的原核生物RNA聚合酶β亚基的抑制剂。对利福平的耐药性由rpoB基因一个小区域内的突变介导。一部分耐药菌株在rpoB中未显示突变，这表明可能存在其他耐药机制，可能是外排泵。异烟肼是一种前体药物，由过氧化氢酶-过氧化物酶KatG激活。katG中的突变在结核分枝杆菌临床分离株中最常见，会导致高水平耐药。尽管如此，异烟肼的分子靶点是InhA，一种参与分枝菌酸生物合成的烯酰-ACP还原酶。其他导致对异烟肼耐药的突变已定位到ndh，一个编码NADH脱氢酶的基因。
