TY - JOUR T1 - Discovery of a cofactor-independent inhibitor of <em>Mycobacterium tuberculosis</em> InhA JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201800025 VL - 1 IS - 3 SP - e201800025 AU - Yi Xia AU - Yasheen Zhou AU - David S Carter AU - Matthew B McNeil AU - Wai Choi AU - Jason Halladay AU - Pamela W Berry AU - Weimin Mao AU - Vincent Hernandez AU - Theresa O'Malley AU - Aaron Korkegian AU - Bjorn Sunde AU - Lindsay Flint AU - Lisa K Woolhiser AU - Michael S Scherman AU - Veronica Gruppo AU - Courtney Hastings AU - Gregory T Robertson AU - Thomas R Ioerger AU - Jim Sacchettini AU - Peter J Tonge AU - Anne J Lenaerts AU - Tanya Parish AU - MRK Alley Y1 - 2018/06/01 UR - https://www.life-science-alliance.org/content/1/3/e201800025.abstract N2 - 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. ER -