Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/6596
Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor
Martínez-Hoyos, María | Perez-Herran, Esther | Gulten, Gulcin | Encinas, Lourdes | Álvarez-Gómez, Daniel | Alvarez, Emilio | Ferrer-Bazaga, Santiago | García-Pérez, Adolfo | Ortega, Fátima | Angulo-Barturen, Iñigo | Rullas, Joaquin ISCIII | Blanco Ruano, Delia | Torres, Pedro | Castañeda, Pablo | Huss, Sophie | Fernández Menéndez, Raquel | González Del Valle, Silvia | Ballell, Lluis | Barros, David | Modha, Sundip | Dhar, Neeraj | Signorino-Gelo, François | McKinney, John D | García-Bustos, Jose Francisco | Lavandera, Jose Luis | Sacchettini, James C | Jimenez, M Soledad ISCIII | Martín-Casabona, Nuria | Castro-Pichel, Julia | Mendoza-Losana, Alfonso
EBioMedicine. 2016; 8:291-301
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.
Animals | Antitubercular Agents | Binding Sites | Catalytic Domain | Disease Models, Animal | Animal Enoyl | Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) | Enzyme Inhibitors | Humans | Mice | Female | Microbial Sensitivity Tests | Microsomes | Models, Molecular | Mutation | Mycobacterium tuberculosis | Protein Binding | Protein Conformation | Tuberculosis | Tuberculosis, Multidrug-Resistant
Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.ebiom.2016.05.006
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