Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA
Abstract
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.
- Authors:
-
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- Anacor Pharmaceuticals, Palo Alto, CA (United States)
- Infectious Disease Research Inst., Seattle, WA (United States)
- Colorado State Univ., Fort Collins, CO (United States)
- Texas A & M Univ., College Station, TX (United States)
- Stony Brook Univ., NY (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- Bill & Melinda Gates Foundation; National Institutes of Health (NIH)
- OSTI Identifier:
- 1545852
- Grant/Contract Number:
- GM102864
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Life Science Alliance
- Additional Journal Information:
- Journal Volume: 1; Journal Issue: 3; Journal ID: ISSN 2575-1077
- Publisher:
- Cold Spring Harbor Laboratory Press
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Microbiology, Virology & Host Pathogen Interaction; Medical Research
Citation Formats
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, and Alley, MRK. Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA. United States: N. p., 2018.
Web. doi:10.26508/lsa.201800025.
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. Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA. United States. https://doi.org/10.26508/lsa.201800025
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, and Alley, MRK. Fri .
"Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA". United States. https://doi.org/10.26508/lsa.201800025. https://www.osti.gov/servlets/purl/1545852.
@article{osti_1545852,
title = {Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA},
author = {Xia, Yi and Zhou, Yasheen and Carter, David S. and McNeil, Matthew B. and Choi, Wai and Halladay, Jason and Berry, Pamela W. and Mao, Weimin and Hernandez, Vincent and O'Malley, Theresa and Korkegian, Aaron and Sunde, Bjorn and Flint, Lindsay and Woolhiser, Lisa K. and Scherman, Michael S. and Gruppo, Veronica and Hastings, Courtney and Robertson, Gregory T. and Ioerger, Thomas R. and Sacchettini, Jim and Tonge, Peter J. and Lenaerts, Anne J. and Parish, Tanya and Alley, MRK},
abstractNote = {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.},
doi = {10.26508/lsa.201800025},
journal = {Life Science Alliance},
number = 3,
volume = 1,
place = {United States},
year = {Fri Jun 01 00:00:00 EDT 2018},
month = {Fri Jun 01 00:00:00 EDT 2018}
}
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Towards a new tuberculosis drug: pyridomycin – nature's isoniazid
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Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor
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Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis
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- Dias, Marcio Vinicius Bertacine; Vasconcelos, Igor Bordin; Prado, Adriane Michele Xavier
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Disseminated disease severity as a measure of virulence of Mycobacterium tuberculosis in the guinea pig model
journal, July 2008
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Enzymic Characterization of the Target for Isoniazid in Mycobacterium tuberculosis
journal, July 1995
- Quemard, Annaiek; Sacchettini, James C.; Dessen, Andrea
- Biochemistry, Vol. 34, Issue 26
Inhibition of InhA, the Enoyl Reductase from Mycobacterium tuberculosis , by Triclosan and Isoniazid †
journal, July 2000
- Parikh, Sapan L.; Xiao, Guoping; Tonge, Peter J.
- Biochemistry, Vol. 39, Issue 26
Roles of Tyrosine 158 and Lysine 165 in the Catalytic Mechanism of InhA, the Enoyl-ACP Reductase from Mycobacterium tuberculosis †
journal, October 1999
- Parikh, Sapan; Moynihan, Daniel P.; Xiao, Guoping
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Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors
journal, February 2017
- Spagnuolo, Lauren A.; Eltschkner, Sandra; Yu, Weixuan
- Journal of the American Chemical Society, Vol. 139, Issue 9
The catalase—peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis
journal, August 1992
- Zhang, Ying; Heym, Beate; Allen, Bryan
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Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid
journal, August 2006
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- Nature Medicine, Vol. 12, Issue 9
The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: Adduct affinity and drug resistance
journal, November 2003
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A Slow, Tight Binding Inhibitor of InhA, the Enoyl-Acyl Carrier Protein Reductase from Mycobacterium tuberculosis
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A new in vivo model to test anti-tuberculosis drugs using fluorescence imaging
journal, May 2012
- Zelmer, A.; Carroll, P.; Andreu, N.
- Journal of Antimicrobial Chemotherapy, Vol. 67, Issue 8
A Mechanism of Drug Action Revealed by Structural Studies of Enoyl Reductase
journal, December 1996
- Baldock, C.; Rafferty, J. B.; Sedelnikova, S. E.
- Science, Vol. 274, Issue 5295
Modification of the NADH of the Isoniazid Target (InhA) from Mycobacterium tuberculosis
journal, January 1998
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- Science, Vol. 279, Issue 5347
Direct inhibitors of InhA are active against Mycobacterium tuberculosis
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Protein Binding of Antimicrobials: Methods for Quantification and for Investigation of its Impact on Bacterial Killing
journal, January 2009
- Beer, Jürgen; Wagner, Claudia Christina; Zeitlinger, Markus
- The AAPS Journal, Vol. 11, Issue 1
Optimisation of Bioluminescent Reporters for Use with Mycobacteria
journal, May 2010
- Andreu, Nuria; Zelmer, Andrea; Fletcher, Taryn
- PLoS ONE, Vol. 5, Issue 5
A Dual Read-Out Assay to Evaluate the Potency of Compounds Active against Mycobacterium tuberculosis
journal, April 2013
- Ollinger, Juliane; Bailey, Mai Ann; Moraski, Garrett C.
- PLoS ONE, Vol. 8, Issue 4
Identification of New Drug Targets and Resistance Mechanisms in Mycobacterium tuberculosis
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Genetic Mutations Associated with Isoniazid Resistance in Mycobacterium tuberculosis: A Systematic Review
journal, March 2015
- Seifert, Marva; Catanzaro, Donald; Catanzaro, Antonino
- PLOS ONE, Vol. 10, Issue 3
Targeting InhA, the FASII Enoyl-ACP Reductase: SAR Studies on Novel Inhibitor Scaffolds
journal, March 2012
- Pan, Pan; J. Tonge, Peter
- Current Topics in Medicinal Chemistry, Vol. 12, Issue 7
Works referencing / citing this record:
Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model
journal, April 2019
- Robertson, Gregory T.; Ektnitphong, Victoria A.; Scherman, Michael S.
- Antimicrobial Agents and Chemotherapy, Vol. 63, Issue 4