Evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of Bacillus anthracis acetohydroxyacid synthase.

Abstract Acetohydroxyacid synthase (AHAS), a potential target for antimicrobial agents, catalyzes the first common step in the biosynthesis of the branched-chain amino acids. The genes of both catalytic and regulatory subunits of AHAS from Bacillus anthracis (Bantx), a causative agent of anthrax, were cloned, overexpressed in Escherichia coli , and purified to homogeneity. To develop novel anti-anthracis drugs that inhibit AHAS, a chemical library was screened, and four chemicals, AVS2087, AVS2093, AVS2387, and AVS2236, were identified as potent inhibitors of catalytic subunit with IC 50 values of 1.0 ± 0.02, 1.0 ± 0.04, 2.1 ± 0.12, and 2.0 ± 0.08 µM, respectively. Further, these four chemicals also showed strong inhibition against reconstituted AHAS with IC 50 values of 0.05 ± 0.002, 0.153 ± 0.004, 1.30 ± 0.10, and 1.29 ± 0.40 µM, respectively. The basic scaffold of the AVS group consists of 1-pyrimidine-2-yl-1 H -[1,2,4]triazole-3-sulfonamide. The potent inhibitor, AVS2093 showed the lowest binding energy, − 8.52 kcal/mol and formed a single hydrogen bond with a distance of 1.973 Ǻ. As the need for novel antibiotic classes to combat bacterial drug resistance increases, the screening of new compounds that act against Bantx-AHAS shows that AHAS is a good target for new anti-anthracis drugs.