Soutter, Holly H., Centrella, Paolo, Clark, Matthew A., Cuozzo, John, Dumelin, Christoph, Guie, Marie-Aude, Habeshian, Sevan, Keefe, Anthony D., Kennedy, Kaitlyn, Sigel, Eric, Troast, Dawn, Zhang, Ying, Ferguson, Andrew, Davies, Gareth, Stead, Eleanor, Breed, Jason, Madhavapeddi, Prashanti and Read, Jon A. (2016) Discovery of novel, co-factor specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology. Proceedings of the National Academy of Sciences.

Abstract

Millions of individuals are infected with and die from tuberculosis (TB) each year. There is an
increasing prevalence of multi-drug resistant (MDR) strains of TB. As such, there is an urgent need to
identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid which
inhibits the essential NADH-dependent enoyl-ACP reductase, InhA. Isoniazid requires activation by the
catalase-peroxidase KatG in order to inhibit InhA. Isoniazid resistance is primarily linked to mutations in
the katG gene. Discovery of novel InhA inhibitors which do not require KatG activation is crucial to
combating MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until
recently, these efforts, despite achieving high potency against the enzyme, have been thwarted by lack
of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with
selection of appropriate physical properties, to identify multiple novel classes of InhA inhibitors with cell
based activity. The utilization of DEX screening allowed for the interrogation of very large compound
libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed
format. Comparison of the enriched library members across various screening conditions allowed for
the identification of co-factor specific inhibitors of InhA which do not require activation by KatG, many
of which had bactericidal activity in cell-based assays.

Item Type:	Article
Date Deposited:	04 Jan 2017 00:45
Last Modified:	04 Jan 2017 00:45
URI:	https://oak.novartis.com/id/eprint/30169