title: 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 microM, 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 microM, respectively. The basic scaffold of the AVS group consists of 1-pyrimidine-2-yl-1H-[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 A. 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.
authors.affiliation: Department of Chemistry and Institute of Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Vinayakumar
authors.initials: V
authors.lastname: Gedi
authors.forename: Kumaresan
authors.initials: K
authors.lastname: Jayaraman
authors.forename: Satish
authors.initials: S
authors.lastname: Kalme
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Park
authors.forename: Hae-Chul
authors.initials: HC
authors.lastname: Park
authors.forename: Im-Joung
authors.initials: IJ
authors.lastname: La
authors.forename: Hoh-Gyu
authors.initials: HG
authors.lastname: Hahn
authors.forename: Moon-Young
authors.initials: MY
authors.lastname: Yoon
mesh_terms: D019880:Aldehyde-Ketone Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000881:Anthrax / Q000188:drug therapy / Q000201:enzymology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000627:therapeutic use; D001408:Bacillus anthracis / Q000201:enzymology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006860:Hydrogen Bonding; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; D019880:Aldehyde-Ketone Transferases