Intrabacterial Metabolism Obscures the Successful Prediction of an InhA Inhibitor of Mycobacterium tuberculosis.

ABSTRACT: Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), kills 1.6 million people annually. To bridge the gap between structure- and cell-based drug discovery strategies, we are pioneering a computer-aided discovery paradigm that merges structure-based virtual screening with ligand-based, machine learning methods trained with cell-based data. This approach successfully identified N-(3-methoxyphenyl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine (JSF-2164) as an inhibitor of purified InhA with whole-cell efficacy versus in vitro cultured M. tuberculosis. When the intrabacterial drug metabolism (IBDM) platform was leveraged, mechanistic studies demonstrated that JSF-2164 underwent a rapid F₄₂₀H₂-dependent biotransformatio

SUBMITTER: Wang X 

PROVIDER: S-EPMC7801736 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature