TY - JOUR
T1 - Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA
AU - Xia, Yi
AU - Zhou, Yasheen
AU - Carter, David S.
AU - McNeil, Matthew B.
AU - Choi, Wai
AU - Halladay, Jason
AU - Berry, Pamela W.
AU - Mao, Weimin
AU - Hernandez, Vincent
AU - O’Malley, Theresa
AU - Korkegian, Aaron
AU - Sunde, Bjorn
AU - Flint, Lindsay
AU - Woolhiser, Lisa K.
AU - Scherman, Michael S.
AU - Gruppo, Veronica
AU - Hastings, Courtney
AU - Robertson, Gregory T.
AU - Ioerger, Thomas R.
AU - Sacchettini, Jim
AU - Tonge, Peter J.
AU - Lenaerts, Anne J.
AU - Parish, Tanya
AU - Alley, M. R.K.
N1 - Publisher Copyright:
© 2018 Xia et al.
PY - 2018
Y1 - 2018
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.
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.
UR - https://www.scopus.com/pages/publications/85057061666
U2 - 10.26508/lsa.201800025
DO - 10.26508/lsa.201800025
M3 - Article
C2 - 30456352
AN - SCOPUS:85057061666
SN - 2575-1077
VL - 1
JO - Life Science Alliance
JF - Life Science Alliance
IS - 3
M1 - e201800025
ER -