EBioMedicine (Jun 2016)
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 Modha,
- Neeraj 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
Affiliations
- María Martínez-Hoyos
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Esther Perez-Herran
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Gulcin Gulten
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
- Lourdes Encinas
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Daniel Álvarez-Gómez
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Emilio Alvarez
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Santiago Ferrer-Bazaga
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Adolfo García-Pérez
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Fátima Ortega
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Iñigo Angulo-Barturen
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Joaquin Rullas-Trincado
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Delia Blanco Ruano
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Pedro Torres
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Pablo Castañeda
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Sophie Huss
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Raquel Fernández Menéndez
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Silvia González del Valle
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Lluis Ballell
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- David Barros
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Sundip Modha
- Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK
- Neeraj Dhar
- School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne 1015, Switzerland
- François Signorino-Gelo
- Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK
- John D. McKinney
- Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK
- Jose Francisco García-Bustos
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Jose Luis Lavandera
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- James C. Sacchettini
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
- M. Soledad Jimenez
- ISCIII, Crta. Majadahonda-Pozuelo Km 2, Majadahonda 28220, Madrid
- Nuria Martín-Casabona
- Department of Microbiology Vall d'Hebron Hospital, Autonomous University Barcelona, Barcelona, Spain
- Julia Castro-Pichel
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- Alfonso Mendoza-Losana
- Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
- DOI
- https://doi.org/10.1016/j.ebiom.2016.05.006
- Journal volume & issue
-
Vol. 8,
no. C
pp. 291 – 301
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.
Keywords
