Inhibitors of the salicylate synthase (MbtI) from Mycobacterium tuberculosis discovered by high-throughput screening.
A simple steady-state kinetic high-throughput assay was developed for the salicylate synthase MbtI from Mycobacterium tuberculosis, which catalyzes the first committed step of mycobactin biosynthesis. The mycobactins are small-molecule iron chelators produced by M. tuberculosis, and their biosynthesis has been identified as a promising target for the development of new antitubercular agents. The assay was miniaturized to a 384-well plate format and high-throughput screening was performed at the National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB). Three classes of compounds were identified comprising the benzisothiazolones (class I), diarylsulfones (class II), and benzimidazole-2-thiones (class III). Each of these compound series was further pursued to investigate their biochemical mechanism and structure-activity relationships. Benzimidazole-2-thione 4 emerged as the most promising inhibitor owing to its potent reversible inhibition.
Center for Drug Design, University of Minnesota, Minneapolis, 55455, USA.
Mahalakshmi
M
Vasan
João
J
Neres
Jessica
J
Williams
Daniel J
DJ
Wilson
Aaron M
AM
Teitelbaum
Rory P
RP
Remmel
Courtney C
CC
Aldrich
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D013450:Sulfones; D013844:Thiazoles; C006699:benzimidazoline-2-thione; D008190:Lyases; C022620:salicylate synthetase; C015699:1,2-benzisothiazoline-3-one