Identification of KasA as the cellular target of an anti-tubercular scaffold.

Autor: Abrahams KA; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Chung CW; GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK., Ghidelli-Disse S; Cellzome-a GSK Company, Meyerhofstrasse 1, 69117 Heidelberg, Germany., Rullas J; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Rebollo-López MJ; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Gurcha SS; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Cox JA; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Mendoza A; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Jiménez-Navarro E; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Martínez-Martínez MS; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Neu M; GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK., Shillings A; GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK., Homes P; GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK., Argyrou A; GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK., Casanueva R; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Loman NJ; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Moynihan PJ; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Lelièvre J; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Selenski C; GlaxoSmithKline, 709 Swedeland Road, PO Box 1539, King of Prussia, Pennsylvania 19406-0939, USA., Axtman M; GlaxoSmithKline, 709 Swedeland Road, PO Box 1539, King of Prussia, Pennsylvania 19406-0939, USA., Kremer L; Centre National de la Recherche Scientifique FRE 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université de Montpellier, 1919 route de Mende, 34293 Montpellier, France.; INSERM, CPBS, 34293 Montpellier, France., Bantscheff M; Cellzome-a GSK Company, Meyerhofstrasse 1, 69117 Heidelberg, Germany., Angulo-Barturen I; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Izquierdo MC; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Cammack NC; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Drewes G; Cellzome-a GSK Company, Meyerhofstrasse 1, 69117 Heidelberg, Germany., Ballell L; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Barros D; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain., Besra GS; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Bates RH; Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2016 Sep 01; Vol. 7, pp. 12581. Date of Electronic Publication: 2016 Sep 01.
DOI: 10.1038/ncomms12581
Abstrakt: Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related β-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.
Databáze: MEDLINE