Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA
| العنوان: | Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA |
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| المؤلفون: | Pamela Berry, Yasheen Zhou, David S. Carter, Jason Halladay, Courtney Hastings, Vincent Hernandez, Bjorn Sunde, Weimin Mao, James C. Sacchettini, Aaron Korkegian, Wai Choi, Peter J. Tonge, Mrk Alley, Anne J. Lenaerts, Yi Xia, Gregory T. Robertson, Michael S. Scherman, Tanya Parish, Lisa K. Woolhiser, Veronica Gruppo, Lindsay Flint, Thomas R. Ioerger, Theresa O’Malley, Matthew B. McNeil |
| المصدر: | Life Science Alliance |
| بيانات النشر: | Life Science Alliance LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Drug, Tuberculosis, Health, Toxicology and Mutagenesis, media_common.quotation_subject, 030106 microbiology, Plant Science, Reductase, Biochemistry, Genetics and Molecular Biology (miscellaneous), Microbiology, Mycobacterium tuberculosis, 03 medical and health sciences, Medicine, Research Articles, media_common, chemistry.chemical_classification, Ecology, biology, business.industry, INHA, Isoniazid, medicine.disease, biology.organism_classification, In vitro, 3. Good health, 030104 developmental biology, Enzyme, chemistry, business, medicine.drug, Research Article |
| الوصف: | AN12855 is a novel cofactor-independent inhibitor of Mycobacterium tuberculosis InhA. AN12855 has potent activity against M. tuberculosis, good oral bioavailability, and comparable efficacy to isoniazid in infection models. 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. |
| اللغة: | English |
| تدمد: | 2575-1077 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b771f3e73b484f275174c0822eeecdd9 http://europepmc.org/articles/PMC6238539 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....b771f3e73b484f275174c0822eeecdd9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 25751077 |
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