Vilchèze Catherine, Wang Feng, Arai Masayoshi, Hazbón Manzour Hernando, Colangeli Roberto, Kremer Laurent, Weisbrod Torin R, Alland David, Sacchettini James C, Jacobs William R
Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Nat Med. 2006 Sep;12(9):1027-9. doi: 10.1038/nm1466. Epub 2006 Aug 13.
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.
异烟肼是最有效的抗结核药物之一，但其确切作用机制仍存在争议。利用专门的连锁转导，将假定靶基因inhA内的一个单点突变等位基因（S94A）导入结核分枝杆菌。inhA（S94A）等位基因足以赋予对异烟肼杀伤和抑制分枝菌酸生物合成的临床相关水平的抗性。如酶学和X射线晶体学分析所示，这种抗性与INH-NAD抑制剂与InhA的结合减少相关，并确定InhA是异烟肼在结核分枝杆菌中作用的主要靶点。
