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

• Published in: Nature communications Vol. 7; no. 1; p. 12581
• Main Authors: Abrahams, Katherine A., Chung, Chun-wa, Ghidelli-Disse, Sonja, Rullas, Joaquín, Rebollo-López, María José, Gurcha, Sudagar S., Cox, Jonathan A. G., 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - antagonists & inhibitors; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - genetics; 631/154/555; 631/326/22; 631/45; 631/535/1266; 64/60; 82/103; 82/58; 82/83; Animals; Antitubercular Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Drug dosages; Drug resistance; Drug Resistance, Bacterial - genetics; Female; Humanities and Social Sciences; Indazoles - pharmacology; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; multidisciplinary; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Optimization; Pharmaceutical sciences; Polymorphism, Single Nucleotide - genetics; Science; Science (multidisciplinary); Sulfonamides - pharmacology; Tuberculosis; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - microbiology; Tuberculosis, Pulmonary - prevention & control; United Kingdom > UK; France
• DOI: 10.1038/ncomms12581
• ISSN: 2041-1723

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. Screens for bactericidal compounds have resulted in promising anti-tubercular hits. Here, the authors analyse in detail the target of an indazole sulfonamide (GSK3011724A), and find that it has a different mode of inhibition compared to other Kas inhibitors of fatty acid biosynthesis in bacteria.