title: Discovery of novel acetohydroxyacid synthase inhibitors as active agents against Mycobacterium tuberculosis by virtual screening and bioassay.
abstract: Acetohydroxyacid synthase (AHAS) has been regarded as a promising drug target against Mycobacterium tuberculosis (MTB) as it catalyzes the biosynthesis of branched-chain amino acids. In this study, 23 novel AHAS inhibitors were identified through molecular docking followed by similarity search. The determined IC(50) values range from 0.385 ± 0.026 μM to >200 μM against bacterium AHAS. Five of the identified compounds show significant in vitro activity against H37Rv strains (MICs in the range of 2.5-80 mg/L) and clinical MTB strains, including MDR and XDR isolates. More impressively, compounds 5 and 7 can enhance the killing ability against macrophages infected pathogen remarkably. This study suggests our discovered inhibitors can be further developed as novel anti-MTB therapeutics targeting AHAS.
authors: Department of Clinical Laboratory, 309 Hospital of Chinese People's Liberation Army, Beijing 100091, China.
authors: Di
authors: D
authors: Wang
authors: Xuelian
authors: X
authors: Zhu
authors: Changjun
authors: C
authors: Cui
authors: Mei
authors: M
authors: Dong
authors: Hualiang
authors: H
authors: Jiang
authors: Zhengming
authors: Z
authors: Li
authors: Zhen
authors: Z
authors: Liu
authors: Weiliang
authors: W
authors: Zhu
authors: Jian-Guo
authors: JG
authors: Wang
mesh_terms: D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D000095:Acetolactate Synthase