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

Autor: Wang X; Department of Pharmacology, Physiology, and Neuroscience , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States., Perryman AL; Department of Pharmacology, Physiology, and Neuroscience , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States., Li SG; Department of Pharmacology, Physiology, and Neuroscience , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States., Paget SD; Department of Pharmacology, Physiology, and Neuroscience , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States., Stratton TP; Department of Pharmacology, Physiology, and Neuroscience , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States., Lemenze A; Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States., Olson AJ; Department of Integrative Structural and Computational Biology , The Scripps Research Institute , Room MB112/Mail Drop MB5, 10550 North Torrey Pines Road , La Jolla , California 92037 , United States., Ekins S; Collaborations in Chemistry , 5616 Hilltop Needmore Road , Fuquay-Varina , North Carolina 27526 , United States., Kumar P; Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States., Freundlich JS; Department of Pharmacology, Physiology, and Neuroscience , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States.; Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens , Rutgers University-New Jersey Medical School , Medical Sciences Building, 185 South Orange Avenue , Newark , New Jersey 07103 , United States.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2019 Dec 13; Vol. 5 (12), pp. 2148-2163. Date of Electronic Publication: 2019 Nov 05.
DOI: 10.1021/acsinfecdis.9b00295
Abstrakt: 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 F 420 H 2 -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.
Databáze: MEDLINE
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