1. Predicting the in vivo mechanism of action for drug leads using NMR metabolomics.
- Author
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Halouska S, Fenton RJ, Barletta RG, and Powers R
- Subjects
- Antitubercular Agents chemistry, Cluster Analysis, Humans, Metabolome drug effects, Mycobacterium Infections, Nontuberculous microbiology, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis metabolism, Predictive Value of Tests, Tuberculosis drug therapy, Tuberculosis microbiology, Antitubercular Agents pharmacology, Drug Discovery methods, Magnetic Resonance Spectroscopy methods, Metabolomics methods, Mycobacterium Infections, Nontuberculous drug therapy, Mycobacterium smegmatis drug effects, Mycobacterium smegmatis metabolism
- Abstract
New strategies are needed to circumvent increasing outbreaks of resistant strains of pathogens and to expand the dwindling supply of effective antimicrobials. A common impediment to drug development is the lack of an easy approach to determine the in vivo mechanism of action and efficacy of novel drug leads. Toward this end, we describe an unbiased approach to predict in vivo mechanisms of action from NMR metabolomics data. Mycobacterium smegmatis, a non-pathogenic model organism for Mycobacterium tuberculosis, was treated with 12 known drugs and 3 chemical leads identified from a cell-based assay. NMR analysis of drug-induced changes to the M. smegmatis metabolome resulted in distinct clustering patterns correlating with in vivo drug activity. The clustering of novel chemical leads relative to known drugs provides a mean to identify a protein target or predict in vivo activity.
- Published
- 2012
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