Inhibitors of the salicylate synthase (Mbti) from Mycobacterium tuberculosis discovered by high-throughput screening

Mahalakshmi Vasan, João Neres, Jessica Williams, Daniel J. Wilson, Aaron M. Teitelbaum, Rory P. Remmel, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2079-2087
Number of pages9
JournalChemMedChem
Volume5
Issue number12
DOIs
StatePublished - Dec 3 2010

Keywords

  • High-throughput screening
  • Mycobactins
  • Salicylate synthase
  • Siderophores
  • Tuberculosis

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