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.
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Martínez-Hoyos
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Perez-Herran
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Gulcin
authors.initials: G
authors.lastname: Gulten
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Encinas
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Álvarez-Gómez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Alvarez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer-Bazaga
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Pérez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Fátima
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Rullas-Trincado
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Delia
authors.initials: D
authors.lastname: Blanco Ruano
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Torres
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Castañeda
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Sophie
authors.initials: S
authors.lastname: Huss
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Fernández Menéndez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: González Del Valle
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Ballell
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.affiliation: Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK.
authors.forename: Sundip
authors.initials: S
authors.lastname: Modha
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhar
authors.affiliation: Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK.
authors.forename: François
authors.initials: F
authors.lastname: Signorino-Gelo
authors.affiliation: Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Jose Francisco
authors.initials: JF
authors.lastname: García-Bustos
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Lavandera
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.affiliation: ISCIII, Crta. Majadahonda-Pozuelo Km 2, Majadahonda 28220, Madrid.
authors.forename: M Soledad
authors.initials: MS
authors.lastname: Jimenez
authors.affiliation: Department of Microbiology Vall d'Hebron Hospital, Autonomous University Barcelona, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Martín-Casabona
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Castro-Pichel
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain. Electronic address: alfonso.x.mendoza@gsk.com.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mendoza-Losana
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D004195:Disease Models, Animal; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008861:Microsomes; D008958:Models, Molecular; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D018088:Tuberculosis, Multidrug-Resistant
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Antibiotic; Bactericidal; Catalase; Drug discovery; InhA; Single-cell imaging; Tuberculosis