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

作者：Martinez Hoyos Maria; Perez Herran Esther; Gulten Gulcin; Encinas Lourdes; Alvarez Gomez Daniel; Alvarez Emilio; Ferrer Bazaga Santiago; Garcia Perez Adolfo; Ortega Fatima; Angulo Barturen Inigo; Rullas Trincado Joaquin; Blanco Ruano Delia; Torres Pedro; Castaneda Pablo; Huss Sophie; Fernandez Menendez Raquel; Gonzalez del Valle Silvia; Ballell Lluis; Barros David; Modha Sundip; Dhar Neeraj; Signorino Gelo Francois; McKinney John D; Francisco Garcia Bustos Jose

来源：EBioMedicine, 2016, 8: 291-301.

DOI：10.1016/j.ebiom.2016.05.006

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

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.

• 出版日期2016-6