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

Katherine A. Abrahams, Chun-wa Chung, Sonja Ghidelli-Disse, Joaquín Rullas, María José Rebollo-López, Sudagar S. Gurcha, Jonathan A. G. Cox, Alfonso Mendoza, Elena Jiménez-Navarro, María Santos Martínez-Martínez, Margarete Neu, Anthony Shillings, Paul Homes, Argyrides Argyrou, Ruth Casanueva, Nicholas J. Loman, Patrick J. Moynihan, Joël Lelièvre, Carolyn Selenski, Matthew Axtman, Laurent Kremer, Marcus Bantscheff, Iñigo Angulo-Barturen, Mónica Cacho Izquierdo, Nicholas C. Cammack, Gerard Drewes, Lluis Ballell, David Barros, Gurdyal S. Besra () and Robert H. Bates ()
Additional contact information
Katherine A. Abrahams: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston
Chun-wa Chung: GlaxoSmithKline
Sonja Ghidelli-Disse: Cellzome—a GSK Company
Joaquín Rullas: Diseases of the Developing World, GlaxoSmithKline
María José Rebollo-López: Diseases of the Developing World, GlaxoSmithKline
Sudagar S. Gurcha: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston
Jonathan A. G. Cox: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston
Alfonso Mendoza: Diseases of the Developing World, GlaxoSmithKline
Elena Jiménez-Navarro: Diseases of the Developing World, GlaxoSmithKline
María Santos Martínez-Martínez: Diseases of the Developing World, GlaxoSmithKline
Margarete Neu: GlaxoSmithKline
Anthony Shillings: GlaxoSmithKline
Paul Homes: GlaxoSmithKline
Argyrides Argyrou: GlaxoSmithKline
Ruth Casanueva: Diseases of the Developing World, GlaxoSmithKline
Nicholas J. Loman: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston
Patrick J. Moynihan: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston
Joël Lelièvre: Diseases of the Developing World, GlaxoSmithKline
Carolyn Selenski: GlaxoSmithKline
Matthew Axtman: GlaxoSmithKline
Laurent Kremer: Centre National de la Recherche Scientifique FRE 3689, Centre d’études d’agents Pathogènes et Biotechnologies pour la Santé, Université de Montpellier
Marcus Bantscheff: Cellzome—a GSK Company
Iñigo Angulo-Barturen: Diseases of the Developing World, GlaxoSmithKline
Mónica Cacho Izquierdo: Diseases of the Developing World, GlaxoSmithKline
Nicholas C. Cammack: Diseases of the Developing World, GlaxoSmithKline
Gerard Drewes: Cellzome—a GSK Company
Lluis Ballell: Diseases of the Developing World, GlaxoSmithKline
David Barros: Diseases of the Developing World, GlaxoSmithKline
Gurdyal S. Besra: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston
Robert H. Bates: Diseases of the Developing World, GlaxoSmithKline

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12581

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