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

  • Martínez-Hoyos M Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Perez-Herran E Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Gulten G Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • Encinas L Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Álvarez-Gómez D Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Alvarez E Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Ferrer-Bazaga S Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • García-Pérez A Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Ortega F Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Angulo-Barturen I Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Rullas-Trincado J Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Blanco Ruano D Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Torres P Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Castañeda P Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Huss S Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Fernández Menéndez R Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • González Del Valle S Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Ballell L Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Barros D Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Modha S Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK.
  • Dhar N School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne 1015, Switzerland.
  • Signorino-Gelo F Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK.
  • McKinney JD Target and Pathway Validation, Molecular Discovery Research, GlaxoSmithKline, Stevenage, Herts, UK.
  • García-Bustos JF Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Lavandera JL Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Sacchettini JC Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • Jimenez MS ISCIII, Crta. Majadahonda-Pozuelo Km 2, Majadahonda 28220, Madrid.
  • Martín-Casabona N Department of Microbiology Vall d'Hebron Hospital, Autonomous University Barcelona, Barcelona, Spain.
  • Castro-Pichel J Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • Mendoza-Losana A Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain. Electronic address: alfonso.x.mendoza@gsk.com.
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  • 2016-07-19
Published in:
  • EBioMedicine. - 2016
Antibiotic
Bactericidal
Catalase
Drug discovery
InhA
Single-cell imaging
Tuberculosis
Animals
Antitubercular Agents
Binding Sites
Catalytic Domain
Disease Models, Animal
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
Enzyme Inhibitors
Female
Humans
Mice
Microbial Sensitivity Tests
Microsomes
Models, Molecular
Mutation
Mycobacterium tuberculosis
Protein Binding
Protein Conformation
Tuberculosis
Tuberculosis, Multidrug-Resistant
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/180458
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