RT Journal Article SR Electronic T1 Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800025 DO 10.26508/lsa.201800025 VO 1 IS 3 A1 Xia, Yi A1 Zhou, Yasheen A1 Carter, David S A1 McNeil, Matthew B A1 Choi, Wai A1 Halladay, Jason A1 Berry, Pamela W A1 Mao, Weimin A1 Hernandez, Vincent A1 O'Malley, Theresa A1 Korkegian, Aaron A1 Sunde, Bjorn A1 Flint, Lindsay A1 Woolhiser, Lisa K A1 Scherman, Michael S A1 Gruppo, Veronica A1 Hastings, Courtney A1 Robertson, Gregory T A1 Ioerger, Thomas R A1 Sacchettini, Jim A1 Tonge, Peter J A1 Lenaerts, Anne J A1 Parish, Tanya A1 Alley, MRK YR 2018 UL http://www.life-science-alliance.org/content/1/3/e201800025.abstract AB 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.