Miesel L, Weisbrod T R, Marcinkeviciene J A, Bittman R, Jacobs W R
Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Bacteriol. 1998 May;180(9):2459-67. doi: 10.1128/JB.180.9.2459-2467.1998.
Isoniazid (INH) is a highly effective drug used in the treatment and prophylaxis of Mycobacterium tuberculosis infections. Resistance to INH in clinical isolates has been correlated with mutations in the inhA, katG, and ahpC genes. In this report, we describe a new mechanism for INH resistance in Mycobacterium smegmatis. Mutations that reduce NADH dehydrogenase activity (Ndh; type II) cause multiple phenotypes, including (i) coresistance to INH and a related drug, ethionamide; (ii) thermosensitive lethality; and (iii) auxotrophy. These phenotypes are corrected by expression of one of two enzymes: NADH dehydrogenase and the NADH-dependent malate dehydrogenase of the M. tuberculosis complex. The genetic data presented here indicate that defects in NADH oxidation cause all of the mutant traits and that an increase in the NADH/NAD+ ratio confers INH resistance.
异烟肼（INH）是一种用于治疗和预防结核分枝杆菌感染的高效药物。临床分离株对INH的耐药性与inhA、katG和ahpC基因的突变有关。在本报告中，我们描述了耻垢分枝杆菌中INH耐药的一种新机制。降低NADH脱氢酶活性（Ndh；II型）的突变会导致多种表型，包括：（i）对INH和相关药物乙硫异烟胺的共同耐药；（ii）温度敏感致死性；以及（iii）营养缺陷型。这些表型可通过两种酶之一的表达得到纠正：NADH脱氢酶和结核分枝杆菌复合群的NADH依赖性苹果酸脱氢酶。此处呈现的遗传数据表明，NADH氧化缺陷导致了所有突变性状，并且NADH/NAD+比值的增加赋予了INH耐药性。
