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


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.

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Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
Additional Information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit Funding: EU FP7 (261378); Bill & Melinda Gates Foundation (OPP1095631; and MRC (MR/K012118/1).
Uncontrolled Keywords: Journal Article
Publication ISSN: 2041-1723
Last Modified: 08 Dec 2023 10:24
Date Deposited: 25 May 2017 08:20
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Related URLs: https://www.ebi ... /entry/pdb/5ld8 (Related URL)
PURE Output Type: Article
Published Date: 2016-09-01
Accepted Date: 2016-07-14
Submitted Date: 2015-11-25
Authors: Abrahams, Katherine A.
Chung, Chun-Wa
Ghidelli-Disse, Sonja
Rullas, Joaquín
Rebollo-López, María José
Gurcha, Sudagar S.
Cox, Jonathan A.G. (ORCID Profile 0000-0001-5208-4056)
Mendoza, Alfonso
Jiménez-Navarro, Elena
Martínez-Martínez, María Santos
Neu, Margarete
Shillings, Anthony
Homes, Paul
Argyrou, Argyrides
Casanueva, Ruth
Loman, Nicholas J.
Moynihan, Patrick J.
Lelièvre, Joël
Selenski, Carolyn
Axtman, Matthew
Kremer, Laurent
Bantscheff, Marcus
Angulo-Barturen, Iñigo
Izquierdo, Mónica Cacho
Cammack, Nicholas C.
Drewes, Gerard
Ballell, Lluis
Barros, David
Besra, Gurdyal S.
Bates, Robert H.



Version: Published Version

License: Creative Commons Attribution

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