Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

作者：Soutter Holly H; Centrella Paolo; Clark Matthew A; Cuozzo John W; Dumelin Christoph E; Guie Marie Aude; Habeshian Sevan; Keefe Anthony D; Kennedy Kaitlyn M; Sigel Eric A; Troast Dawn M; Zhang Ying; Ferguson Andrew D; Davies Gareth; Stead Eleanor R; Breed Jason; Madhavapeddi Prashanti; Read Jon A

来源：Proceedings of the National Academy of Sciences, 2016, 113(49): E7880-E7889.

DOI：10.1073/pnas.1610978113

<jats:p>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 <jats:italic>katG</jats:italic> 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 (10<jats:sup>11</jats:sup> 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 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.</jats:p>

• 出版日期2016-12-6