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 Yi Xia A1 Yasheen Zhou A1 David S Carter A1 Matthew B McNeil A1 Wai Choi A1 Jason Halladay A1 Pamela W Berry A1 Weimin Mao A1 Vincent Hernandez A1 Theresa O'Malley A1 Aaron Korkegian A1 Bjorn Sunde A1 Lindsay Flint A1 Lisa K Woolhiser A1 Michael S Scherman A1 Veronica Gruppo A1 Courtney Hastings A1 Gregory T Robertson A1 Thomas R Ioerger A1 Jim Sacchettini A1 Peter J Tonge A1 Anne J Lenaerts A1 Tanya Parish A1 MRK Alley YR 2018 UL https://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.