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 AxtmanLaurent Kremer, Marcus Bantscheff, Iñigo Angulo-Barturen, Mónica Cacho Izquierdo, Nicholas C. Cammack, Gerard Drewes, Lluis Ballell, David Barros, Gurdyal S. Besra*, Robert H. Bates

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

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.

Original languageEnglish
Article number12581
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 1 Sep 2016
Externally publishedYes

Bibliographical note

Funding Information:
The research leading to these results has received funding from the European Union? 7th framework programme (FP7-2007-2013) under Grant Agreement No 261378, the Bill & Melinda Gates Foundation (OPP1095631), and the Medical Research Council (MR/K012118/1).

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