Unknown

Dataset Information

0

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 biotransformation within M. tuberculosis to afford intrabacterial nitric oxide and two amines, identified as JSF-3616 and JSF-3617. Thus, metabolism of JSF-2164 obscured the InhA inhibition phenotype within cultured M. tuberculosis. This study demonstrates a new docking/Bayesian computational strategy to combine cell- and target-based drug screening and the need to probe intrabacterial metabolism when clarifying the antitubercular mechanism of action.

SUBMITTER: Wang X 

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

REPOSITORIES: biostudies-literature

altmetric image

Publications

Intrabacterial Metabolism Obscures the Successful Prediction of an InhA Inhibitor of <i>Mycobacterium tuberculosis</i>.

Wang Xin X   Perryman Alexander L AL   Li Shao-Gang SG   Paget Steve D SD   Stratton Thomas P TP   Lemenze Alex A   Olson Arthur J AJ   Ekins Sean S   Kumar Pradeep P   Freundlich Joel S JS  

ACS infectious diseases 20191105 12


Tuberculosis, caused by <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>), 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 <i>N</i>-(3-methoxyphenyl)-7-nitrobenzo[<i>c</i>][1,2,5]oxadiazol-4-amine (JSF-2164) as an  ...[more]

Similar Datasets

| S-EPMC6238539 | biostudies-literature
| S-EPMC5588031 | biostudies-literature
| S-EPMC2538620 | biostudies-literature
| S-EPMC3215101 | biostudies-literature
| S-EPMC2863195 | biostudies-literature
| S-EPMC4383039 | biostudies-literature
| S-EPMC4026456 | biostudies-literature
| S-EPMC7232676 | biostudies-literature
| S-EPMC4607644 | biostudies-literature
| S-EPMC4386068 | biostudies-literature