期刊
EBIOMEDICINE
卷 8, 期 -, 页码 291-301出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2016.05.006
关键词
Tuberculosis; Antibiotic; InhA; Bactericidal; Drug discovery; Single-cell imaging; Catalase
资金
- GlaxoSmithKline R&D the Global Alliance for TB Drug Development
- European Union under Orchid grant [261378]
Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment. (C) 2016 The Authors. Published by Elsevier B.V.
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