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

DOI: 10.1038/ncomms12581 DOI Help

Authors: Katherine A. Abrahams (University of Birmingham) , Chun-Wa Chung (GlaxoSmithKline) , Sonja Ghidelli-Disse (Cellzome—a GSK Company) , Joaquín Rullas (GlaxoSmithKline) , María José Rebollo-López (GlaxoSmithKline) , Sudagar S. Gurcha (University of Birmingham) , Jonathan A. G. Cox (University of Birmingham) , Alfonso Mendoza (GlaxoSmithKline) , Elena Jiménez-Navarro (GlaxoSmithKline) , María Santos Martínez-Martínez (GlaxoSmithKline) , Margarete Neu (GlaxoSmithKline) , Anthony Shillings (GlaxoSmithKline) , Paul Homes (GlaxoSmithKline) , Argyrides Argyrou (GlaxoSmithKline) , Ruth Casanueva (GlaxoSmithKline) , Nicholas J. Loman (University of Birmingham) , Patrick J. Moynihan (University of Birmingham) , Joël Lelièvre (GlaxoSmithKline) , Carolyn Selenski (GlaxoSmithKline) , Matthew Axtman (GlaxoSmithKline) , Laurent Kremer , Marcus Bantscheff (Université de Montpellier) , Iñigo Angulo-Barturen (GlaxoSmithKline) , Mónica Cacho Izquierdo (GlaxoSmithKline) , Nicholas C. Cammack (GlaxoSmithKline) , Gerard Drewes (Cellzome—a GSK Company) , Lluis Ballell (GlaxoSmithKline) , David Barros (GlaxoSmithKline) , Gurdyal S. Besra (University of Birmingham) , Robert H. Bates (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 7

State: Published (Approved)
Published: September 2016
Diamond Proposal Number(s): 12279

Open Access Open Access

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.

Journal Keywords: Antimicrobials; Biochemistry; Target identification; X-ray crystallography

Diamond Keywords: Tuberculosis (TB); Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 07/12/2016 13:07


Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)