NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis
NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis
复制标题
DOI：
10.1128/jb.180.9.2459-2467.1998
复制
发表时间：
1998-05-01
影响因子：
3.2
通讯作者：
Jacobs, WR
中科院分区：
文献类型：
--
作者：
Miesel, L;Weisbrod, TR;Jacobs, WR
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INH耐药的新机制。降低NADH脱氢酶活性的突变（Ndh； II型）导致多种表型，包括(i)对INH和相关药物乙硫酰胺的共抗性；（ii）热敏致死性；（三）营养不良。这些表型通过两种酶之一的表达来纠正：结核分枝杆菌复合体的NADH脱氢酶和NADH依赖的苹果酸脱氢酶。本文提供的遗传数据表明，NADH氧化缺陷导致了所有突变性状，NADH/NAD（+）比值的增加赋予了INH抗性。
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.