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 ModhaJose Francisco García-Bustos

Research output: Contribution to journalArticleResearchpeer-review

41 Citations (Scopus)

Abstract

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
Number of pages11
JournalEBioMedicine
Volume8
DOIs
Publication statusPublished - Jun 2016
Externally publishedYes

Keywords

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

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