Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

María Martínez-Hoyos, Esther Perez-Herran, Gulcin Gulten, Lourdes Encinas, Daniel Álvarez-Gómez, Emilio Alvarez, Santiago Ferrer-Bazaga, Adolfo García-Pérez, Fátima Ortega, Iñigo Angulo-Barturen, Joaquin Rullas-Trincado, Delia Blanco Ruano, Pedro Torres, Pablo Castañeda, Sophie Huss, Raquel Fernández Menéndez, Silvia González del Valle, Lluis Ballell, David Barros, Sundip ModhaNeeraj Dhar, François Signorino-Gelo, John D. McKinney, Jose Francisco García-Bustos, Jose Luis Lavandera, James C. Sacchettini, M. Soledad Jimenez, Nuria Martín-Casabona, Julia Castro-Pichel, Alfonso Mendoza-Losana

    Research output: Contribution to journalArticleResearchpeer-review

    34 Citations (Scopus)

    Abstract

    © 2016 The Authors. 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.
    Original languageEnglish
    Pages (from-to)291-301
    JournalEBioMedicine
    Volume8
    DOIs
    Publication statusPublished - 1 Jun 2016

    Keywords

    • Antibiotic
    • Bactericidal
    • Catalase
    • Drug discovery
    • InhA
    • Single-cell imaging
    • Tuberculosis

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