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.
Tuberculosis; Antibiotic; InhA; Bactericidal; Drug discovery; Single-cell imaging; Catalase
Citation: María Martínez-Hoyos, Esther Perez-Herran, Gulcin Gulten, Lourdes Encinas, Daniel Alvarez-Gomez, Emilio Alvarez, Santiago Ferrer-Bazaga, Adolfo Garcia-Perez, Fatima Ortega, Inigo Angulo-Barturen, Joaquin Rullas-Trincado, Delia Blanco Ruano, Pedro Torres, Pablo Castaneda, Sophie Huss, Raquel Fernández Menendez, Silvia Gonzalez del Valle, Lluis Ballell, David Barros, Sundip Modha, Neeraj Dhar, Francois Signorino-Geloc, John D. McKinney, Jose Francisco García-Bustos Antitubercular Drugs For An Old Target: GSK693 As A Promising InhA Direct Inhibitor http://dx.doi.org/10.1016/j.ebiom.2016.05.006
Received: 4 February 2016, Revised: 29 April 2016, Accepted: 3 May 2016, Available online: 8 May 2016
Copyright: © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Standard antitubercular treatment consists of a combination of four compounds (isoniazid, rifampicin, ethambutol, and pyrazinamide) during 2 months that eliminate all the fast growing bacteria and 4 additional months of isoniazid and rifampicin that complete patient cure.
The treatment is long, complex, and has important adverse effects, so the lack of adherence is not unusual, leading to suboptimal responses (failure and relapse), emergence of resistance, and continuous spread of the disease. The presence of rapidly bactericidal compounds like isoniazid as part of the combination has a high impact in blocking transmission and improving the health of infected people.
We have demonstrated that a direct inhibitor on InhA can retain the outstanding profile of isoniazid and considering the DMPK parameters of both compounds the antitubercular effect is achieved at similar exposures of free drug proving our initial hypothesis and overcoming resistances mediated by KatG. GSK693 has demonstrated in vivo efficacy comparable to the marketed drug isoniazid without being a pro-drug, thus overcoming most of INH associated liabilities. Besides, its improved property profile should translate into a safer treatment. Overall, this achievement opens the door to the development of a direct inhibitor of the enoyl-ACP reductase (InhA) as an attractive drug candidate for the therapy of Tuberculosis.
The research leading to these results has received funding from GlaxoSmithKline 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.
Conflict of interest
All the authors confirm the absence of any conflict of interest.