Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid

被引：242

作者：

Vilcheze, Catherine

Wang, Feng

Arai, Masayoshi

Hazbon, Manzour Hernando

Colangeli, Roberto

Kremer, Laurent

Weisbrod, Torin R.

Alland, David

Sacchettini, James C.

Jacobs, William R., Jr.

机构：

[1] Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Howard Hughes Med Inst, Bronx, NY 10461 USA

[2] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA

[3] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Div Infect Dis, Newark, NJ 07103 USA

[4] Univ Med & Dent New Jersey, New Jersey Med Sch, Ruy V Lourenco Ctr Study Emerging & Reemerging Pa, Newark, NJ 07103 USA

[5] Univ Montpellier 2, CNRS, Lab Dynam Mol Interact Membranaires, UMR 5539, F-34095 Montpellier 05, France

来源：

NATURE MEDICINE | 2006年 / 12卷 / 09期

关键词：

D O I：

10.1038/nm1466

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Isoniazid is one of the most effective antituberculosis drugs, yet its precise mechanism of action is still controversial. Using specialized linkage transduction, a single point mutation allele (S94A) within the putative target gene inhA was transferred in Mycobacterium tuberculosis. The inhA(S94A) allele was sufficient to confer clinically relevant levels of resistance to isoniazid killing and inhibition of mycolic acid biosynthesis. This resistance correlated with the decreased binding of the INH-NAD inhibitor to InhA, as shown by enzymatic and X-ray crystallographic analyses, and establishes InhA as the primary target of isoniazid action in M. tuberculosis.

引用

页码：1027 / 1029

页数：3

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