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.
Highlights
Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis
On-going efforts to combat drug-resistant TB have taken many forms including the re-purposing of broad spectrum antibacterials, target-based programs on mycobacterial enzymes, efforts to optimize or re-invent known TB drugs, and phenotypic screening approaches, which have all been widely reported[4,27,28,29,30,31,32]
This product is channelled to KasA of the fatty acid synthase (FAS)-II system[33]
Summary
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 singlenucleotide polymorphisms in the essential Mycobacterium tuberculosis b-ketoacyl synthase (kas) A gene. The lack of target engagement of the related b-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. In 2013, the World Health Organization (WHO) recorded B480,000 new cases of multidrug-resistant (MDR)-TB, resistant to both the front-line drugs, isoniazid (INH) and rifampicin (RIF)[3] Without these two frontline drugs, MDR-TB generally requires 24 months of treatment with a variety of second-line antibiotics, which are poorly tolerated. This level of ED99 is only moderately higher than most of the gold standard TB drugs[11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
