Antitubercular drugs for an old target : GSK693 as a promising InhA direct inhibitor
Martínez-Hoyos, María (GlaxoSmithKline (Madrid))
Perez-Herran, Esther (GlaxoSmithKline (Madrid))
Gulten, Gulcin (Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA)
Encinas, Lourdes (GlaxoSmithKline (Madrid))
Álvarez-Gómez, Daniel (GlaxoSmithKline (Madrid))
Alvarez, Emilio (GlaxoSmithKline (Madrid))
Ferrer-Bazaga, Santiago (GlaxoSmithKline (Madrid))
García-Pérez, Adolfo (GlaxoSmithKline (Madrid))
Ortega, Fátima (GlaxoSmithKline (Madrid))
Angulo-Barturen, Iñigo (GlaxoSmithKline (Madrid))
Rullas-Trincado, Joaquin (GlaxoSmithKline (Madrid))
Blanco Ruano, Delia (GlaxoSmithKline (Madrid))
Torres, Pedro (GlaxoSmithKline (Madrid))
Castañeda, Pablo (GlaxoSmithKline (Madrid))
Huss, Sophie (GlaxoSmithKline (Madrid))
Fernández Menéndez, Raquel (GlaxoSmithKline (Madrid))
González del Valle, Silvia (GlaxoSmithKline (Madrid))
Ballell, Lluis (GlaxoSmithKline (Madrid))
Barros, David (GlaxoSmithKline (Madrid))
Modha, Sundip (Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK)
Dhar, Neeraj (School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne 1015, Switzerland)
Signorino-Gelo, François (Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK)
McKinney, John D. (Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK)
García-Bustos, Jose Francisco (GlaxoSmithKline (Madrid))
Lavandera, Jose Luis (GlaxoSmithKline (Madrid))
Sacchettini, James C. (Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA)
Jimenez, M. Soledad (Instituto de Salud Carlos III)
Martín-Casabona, Nuria (Hospital Universitari Vall d'Hebron)
Castro-Pichel, Julia (GlaxoSmithKline (Madrid))
Mendoza-Losana, Alfonso (GlaxoSmithKline (Madrid))
Universitat Autònoma de Barcelona

Date:	2016
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. Last year, Mycobacterium tuberculosis had the doubtful honor of being the top infectious killer worldwide. The current 6-month treatment, which was developed more than 30 years ago, has saved million of lives but bears the drawback of poor compliance; hence, the world needs a new shorter and safer TB treatment. The biochemical screening of GSK compound library performed by Martinez et al. has identified new KatG-independent inhibitor of InhA active against M(X)DR Mtb strains, good drug-like properties, and in vivo activity similar to isoniazid overcoming the resistance and toxicological issues of the former drug.
Note:	Altres ajuts: The research leading to these results has received funding fromGlaxoSmithKline R&D the Global Alliance for TB Drug Development, and from the European Union's 7th framework program (FP7-2007-2013) under the Orchid grant agreement no.261378.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Tuberculosis ; Antibiotic ; InhA ; Bactericidal ; Drug discovery ; Single-cell imaging ; Catalase
Published in:	EBioMedicine, Vol. 8 (may 2016) , p. 291-301, ISSN 2352-3964

DOI: 10.1016/j.ebiom.2016.05.006
PMID: 27428438

11 p, 779.0 KB

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