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

Author

Listed:
  • 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
    INSERM, CPBS)

  • 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)

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.

Suggested Citation

  • 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 Sant, 2016. "Identification of KasA as the cellular target of an anti-tubercular scaffold," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12581
    DOI: 10.1038/ncomms12581
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