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Title: Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA

Journal Article · · Life Science Alliance
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  1. Anacor Pharmaceuticals, Palo Alto, CA (United States)
  2. Infectious Disease Research Inst., Seattle, WA (United States)
  3. Colorado State Univ., Fort Collins, CO (United States)
  4. Texas A & M Univ., College Station, TX (United States)
  5. Stony Brook Univ., NY (United States)
+ Show Author Affiliations

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
Citation Metrics:
Cited by: 21 works
Citation information provided by
Web of Science

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Cited By (1)

Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model journal April 2019

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