Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA
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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.
complete list of authors
Xia, Yi||Zhou, Yasheen||Carter, David S||McNeil, Matthew B||Choi, Wai||Halladay, Jason||Berry, Pamela W||Mao, Weimin||Hernandez, Vincent||O'Malley, Theresa||Korkegian, Aaron||Sunde, Bjorn||Flint, Lindsay||Woolhiser, Lisa K||Scherman, Michael S||Gruppo, Veronica||Hastings, Courtney||Robertson, Gregory T||Ioerger, Thomas R||Sacchettini, Jim||Tonge, Peter J||Lenaerts, Anne J||Parish, Tanya||Alley, Mrk