Inhibitors of the Salicylate Synthase (MbtI) from Mycobacterium tuberculosis Discovered by High-Throughput Screening

被引:47
作者
Vasan, Mahalakshmi [1 ]
Neres, Joao [1 ]
Williams, Jessica [1 ]
Wilson, Daniel J. [1 ]
Teitelbaum, Aaron M. [2 ]
Remmel, Rory P. [2 ]
Aldrich, Courtney C. [1 ]
机构
[1] Univ Minnesota, Ctr Drug Design, Acad Hlth Ctr, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA
关键词
high-throughput screening; mycobactins; salicylate synthase; siderophores; tuberculosis; CHORISMATE-UTILIZING ENZYMES; PHOSPHATASE 1B PTP1B; IRON ACQUISITION; 4-AMINO-4-DEOXYCHORISMATE SYNTHASE; ISOCHORISMATE SYNTHASE; SIDEROPHORE MYCOBACTIN; ISOTHIAZOLONE BIOCIDES; REDOX REGULATION; IDENTIFICATION; BIOSYNTHESIS;
D O I
10.1002/cmdc.201000275
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:2079 / 2087
页数:9
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