title: Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology.
abstract: Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. 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-acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts 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 classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.
authors.affiliation: Therapeutic Discovery Sciences, X-Chem Pharmaceuticals, Waltham, MA 02453; hsoutter@x-chemrx.com Jon.Read@astrazeneca.com.
authors.forename: Holly H
authors.initials: HH
authors.lastname: Soutter
authors.affiliation: Discovery Chemistry, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Paolo
authors.initials: P
authors.lastname: Centrella
authors.affiliation: X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Clark
authors.affiliation: Therapeutic Discovery Sciences, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: John W
authors.initials: JW
authors.lastname: Cuozzo
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Christoph E
authors.initials: CE
authors.lastname: Dumelin
authors.affiliation: Scientific Computing, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Guie
authors.affiliation: Discovery Chemistry, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Sevan
authors.initials: S
authors.lastname: Habeshian
authors.affiliation: Lead Discovery, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Keefe
authors.affiliation: Discovery Chemistry, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Kaitlyn M
authors.initials: KM
authors.lastname: Kennedy
authors.affiliation: Scientific Computing, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sigel
authors.affiliation: Morphic Therapeutic, Waltham, MA 02451.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Troast
authors.affiliation: Discovery Chemistry, X-Chem Pharmaceuticals, Waltham, MA 02453.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Waltham, MA 02451.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Macclesfield SK10 4TG, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Davies
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Macclesfield SK10 4TG, United Kingdom.
authors.forename: Eleanor R
authors.initials: ER
authors.lastname: Stead
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.affiliation: AstraZeneca India Private Ltd., Hebbal, Bangalore 560 024, India.
authors.forename: Prashanti
authors.initials: P
authors.lastname: Madhavapeddi
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge CB4 0WG, United Kingdom; hsoutter@x-chemrx.com Jon.Read@astrazeneca.com.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Read
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries
chemical_list: D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: DNA-encoded X-Chem technology; DNA-encoded libraries; InhA; Mycobacterium tuberculosis; multidrug resistance