Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA
- Anacor Pharmaceuticals, Palo Alto, CA (United States)
- Infectious Disease Research Inst., Seattle, WA (United States)
- Colorado State Univ., Fort Collins, CO (United States)
- Texas A & M Univ., College Station, TX (United States)
- Stony Brook Univ., NY (United States)
New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis. The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- Bill & Melinda Gates Foundation; National Institutes of Health (NIH)
- Grant/Contract Number:
- GM102864
- OSTI ID:
- 1545852
- Journal Information:
- Life Science Alliance, Vol. 1, Issue 3; ISSN 2575-1077
- Publisher:
- Cold Spring Harbor Laboratory PressCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model
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journal | April 2019 |
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