Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid
Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid
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DOI：
10.1038/nm1466
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发表时间：
2006-09-01
期刊：
影响因子：
82.9
通讯作者：
Jacobs, William R., Jr.
中科院分区：
文献类型：
--
作者：
Vilcheze, Catherine;Wang, Feng;Jacobs, William R., Jr.
异烟肼是最有效的抗结核药物之一，但其确切的作用机制仍有争议。使用专门的连锁转导，一个单一的点突变等位基因（S94 A）内的推定的靶基因inhA转移到结核分枝杆菌。inhA（S94 A）等位基因足以赋予临床相关水平的耐异烟肼杀死和抑制分枝菌酸生物合成。这种耐药性与INH-NAD抑制剂与InhA的结合减少相关，如酶和X射线晶体学分析所示，并确定InhA为M中异烟肼作用的主要靶点。结核
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.