Article

Predicting the in vivo mechanism of action for drug leads using NMR metabolomics.

ACS Chemical Biology (impact factor: 6.45). 01/2012; 7(1):166-71. DOI:10.1021/cb200348m
Source: PubMed

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.

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Keywords

3 chemical
 
cell-based assay
 
distinct clustering patterns correlating
 
drug development
 
drug-induced changes
 
drugs
 
easy approach
 
effective antimicrobials
 
M. smegmatis metabolome
 
Mycobacterium smegmatis
 
Mycobacterium tuberculosis
 
New strategies
 
NMR metabolomics data
 
non-pathogenic model organism
 
novel drug
 
protein target
 
resistant strains
 
unbiased approach
 
vivo activity
 
vivo drug activity