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; Jose Francisco García-Bustos

doi:10.1016/j.ebiom.2016.05.006

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 ModhaJose Francisco García-Bustos

Research output: Contribution to journal › Article › Research › peer-review

82 Citations (Scopus)

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.

Original language	English
Pages (from-to)	291-301
Number of pages	11
Journal	EBioMedicine
Volume	8
DOIs	https://doi.org/10.1016/j.ebiom.2016.05.006
Publication status	Published - Jun 2016
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antibiotic
Bactericidal
Catalase
Drug discovery
InhA
Single-cell imaging
Tuberculosis

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Martínez-Hoyos, M., Perez-Herran, E., Gulten, G., Encinas, L., Álvarez-Gómez, D., Alvarez, E., Ferrer-Bazaga, S., García-Pérez, A., Ortega, F., Angulo-Barturen, I., Rullas-Trincado, J., Blanco Ruano, D., Torres, P., Castañeda, P., Huss, S., Fernández Menéndez, R., González del Valle, S., Ballell, L., Barros, D., ... García-Bustos, J. F. (2016). Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine, 8, 291-301. https://doi.org/10.1016/j.ebiom.2016.05.006

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title = "Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor",

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 = "Antibiotic, Bactericidal, Catalase, Drug discovery, InhA, Single-cell imaging, Tuberculosis",

author = "Mar{\'i}a Mart{\'i}nez-Hoyos and Esther Perez-Herran and Gulcin Gulten and Lourdes Encinas and Daniel {\'A}lvarez-G{\'o}mez and Emilio Alvarez and Santiago Ferrer-Bazaga and Adolfo Garc{\'i}a-P{\'e}rez and F{\'a}tima Ortega and I{\~n}igo Angulo-Barturen and Joaquin Rullas-Trincado and \{Blanco Ruano\}, Delia and Pedro Torres and Pablo Casta{\~n}eda and Sophie Huss and \{Fern{\'a}ndez Men{\'e}ndez\}, Raquel and \{Gonz{\'a}lez del Valle\}, Silvia and Lluis Ballell and David Barros and Sundip Modha and Garc{\'i}a-Bustos, \{Jose Francisco\}",

year = "2016",

month = jun,

doi = "10.1016/j.ebiom.2016.05.006",

language = "English",

volume = "8",

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journal = "EBioMedicine",

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Martínez-Hoyos, M, Perez-Herran, E, Gulten, G, Encinas, L, Álvarez-Gómez, D, Alvarez, E, Ferrer-Bazaga, S, García-Pérez, A, Ortega, F, Angulo-Barturen, I, Rullas-Trincado, J, Blanco Ruano, D, Torres, P, Castañeda, P, Huss, S, Fernández Menéndez, R, González del Valle, S, Ballell, L, Barros, D, Modha, S & García-Bustos, JF 2016, 'Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor', EBioMedicine, vol. 8, pp. 291-301. https://doi.org/10.1016/j.ebiom.2016.05.006

TY - JOUR

T1 - Antitubercular drugs for an old target

T2 - GSK693 as a promising InhA direct inhibitor

AU - Martínez-Hoyos, María

AU - Perez-Herran, Esther

AU - Gulten, Gulcin

AU - Encinas, Lourdes

AU - Álvarez-Gómez, Daniel

AU - Alvarez, Emilio

AU - Ferrer-Bazaga, Santiago

AU - García-Pérez, Adolfo

AU - Ortega, Fátima

AU - Angulo-Barturen, Iñigo

AU - Rullas-Trincado, Joaquin

AU - Blanco Ruano, Delia

AU - Torres, Pedro

AU - Castañeda, Pablo

AU - Huss, Sophie

AU - Fernández Menéndez, Raquel

AU - González del Valle, Silvia

AU - Ballell, Lluis

AU - Barros, David

AU - Modha, Sundip

AU - García-Bustos, Jose Francisco

PY - 2016/6

Y1 - 2016/6

N2 - 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.

AB - 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.

KW - Antibiotic

KW - Bactericidal

KW - Catalase

KW - Drug discovery

KW - InhA

KW - Single-cell imaging

KW - Tuberculosis

UR - https://www.scopus.com/pages/publications/84975483714

U2 - 10.1016/j.ebiom.2016.05.006

DO - 10.1016/j.ebiom.2016.05.006

M3 - Article

AN - SCOPUS:84975483714

SN - 2352-3964

VL - 8

SP - 291

EP - 301

JO - EBioMedicine

JF - EBioMedicine

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

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