烟酰胺腺嘌呤二核苷酸（NADH）脱氢酶缺陷赋予耻垢分枝杆菌对异烟肼的抗性和条件致死性。
NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis.
作者信息
Miesel L, Weisbrod T R, Marcinkeviciene J A, Bittman R, Jacobs W R
机构信息
Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
出版信息
J Bacteriol. 1998 May;180(9):2459-67. doi: 10.1128/JB.180.9.2459-2467.1998.
Abstract
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.
摘要
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。
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本文引用的文献
1
Bacterial resistance studies with derivatives of isonicotinic acid.异烟酸衍生物的细菌耐药性研究
Am Rev Tuberc. 1952 Jun;65(6):768-70.
2
3
Hydrazine derivatives of isonicotinic acid (rimifon marsilid) in the treatment of active progressive caseous-pneumonic tuberculosis; a preliminary report.异烟酸肼衍生物（雷米封、异烟酰胺）治疗进展期活动性干酪性肺炎型肺结核的初步报告
Am Rev Tuberc. 1952 Apr;65(4):402-28. doi: 10.1164/art.1952.65.4.402.
4
Catalase and peroxidase in mycobacteria. Possible relationship to the mode of action of isoniazid.分枝杆菌中的过氧化氢酶和过氧化物酶。与异烟肼作用方式的可能关系。
Am Rev Respir Dis. 1960 Jan;81:68-78. doi: 10.1164/arrd.1960.81.1P1.68.
5
Isoniazid-resistance and catalase activity of tubercle bacilli; a preliminary report.结核杆菌的异烟肼耐药性与过氧化氢酶活性；初步报告。
Am Rev Tuberc. 1954 Mar;69(3):471-2. doi: 10.1164/art.1954.69.3.471.
6
Some observations on the pathogenicity of isoniazid-resistant variants of tubercle bacilli.关于结核杆菌异烟肼耐药变异株致病性的一些观察
Science. 1953 Sep 11;118(3063):297-9. doi: 10.1126/science.118.3063.297.
7
Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis.结核分枝杆菌异烟肼靶点（InhA）的烟酰胺腺嘌呤二核苷酸（NADH）修饰
Science. 1998 Jan 2;279(5347):98-102. doi: 10.1126/science.279.5347.98.
8
Effects of overexpression of the alkyl hydroperoxide reductase AhpC on the virulence and isoniazid resistance of Mycobacterium tuberculosis.烷基过氧化氢还原酶AhpC过表达对结核分枝杆菌毒力和异烟肼耐药性的影响
Infect Immun. 1997 Apr;65(4):1395-401. doi: 10.1128/iai.65.4.1395-1401.1997.
9
Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: a blind study at reference laboratory level.结核分枝杆菌中异烟肼和利福平耐药性的基因分型评估：参考实验室水平的一项盲法研究
J Clin Microbiol. 1997 Mar;35(3):719-23. doi: 10.1128/jcm.35.3.719-723.1997.
10
Drug-resistant tuberculosis: review of the worldwide situation and the WHO/IUATLD Global Surveillance Project. International Union Against Tuberculosis and Lung Disease.耐药结核病：全球形势回顾与世卫组织/国际防痨和肺部疾病联盟全球监测项目。国际防痨和肺部疾病联盟。
Clin Infect Dis. 1997 Jan;24 Suppl 1:S121-30. doi: 10.1093/clinids/24.supplement_1.s121.
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