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

Abrahams, Katherine A.; Mendoza Losana, Alfonso

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

dc.affiliation.dpto	UC3M. Departamento de Bioingeniería	es
dc.affiliation.grupoinv	UC3M. Grupo de Investigación: Biomedical Imaging and Instrumentation Group	es
dc.contributor.author	Abrahams, Katherine A.
dc.contributor.author	Mendoza Losana, Alfonso
dc.contributor.funder	European Commission	es
dc.date.accessioned	2023-11-15T14:22:55Z
dc.date.available	2023-11-15T14:22:55Z
dc.date.issued	2016-09-01
dc.description.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 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-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.	en
dc.description.sponsorship	The research leading to these results has received funding from the European Unionś 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).	en
dc.identifier.bibliographicCitation	Abrahams, K. A., Chung, C., Ghidelli-Disse, S., Rullas, J., Rebollo-López, M. J., Gurcha, S. S., Cox, J. A. G., Mendoza, A., Jiménez-Navarro, E., Martínez-Martínez, M. S., Neu, M., Shillings, A., Homes, P., Argyrou, A., Casanueva, R., Loman, N. J., Moynihan, P. J., Lelièvre, J., Selenski, C., … Bates, R. H. (2016). Identification of KasA as the cellular target of an anti-tubercular scaffold. Nature Communications, 7 (1).	en
dc.identifier.doi	https://doi.org/10.1038/ncomms12581
dc.identifier.issn	2041-1723
dc.identifier.publicationissue	12581	es
dc.identifier.publicationtitle	Nature Communications	en
dc.identifier.publicationvolume	7	es
dc.identifier.uri	https://hdl.handle.net/10016/38870
dc.identifier.uxxi	AR/0000030703
dc.language.iso	eng	es
dc.publisher	Springer	es
dc.relation.projectID	info:eu-repo/grantAgreement/EC/FP7/261378	es
dc.rights	© The authors	es
dc.rights	Atribución 3.0 España	*
dc.rights.accessRights	open access	es
dc.rights.uri	http://creativecommons.org/licenses/by/3.0/es/	*
dc.subject.eciencia	Medicina	es
dc.title	Identification of KasA as the cellular target of an anti-tubercular scaffold	en
dc.type	research article	*
dc.type.hasVersion	VoR	*
dspace.entity.type	Publication