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Metabolomics Reveal d-Alanine:d-Alanine Ligase As the Target of d-Cycloserine in Mycobacterium tuberculosis.

Abstract：

:Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic action of d-cycloserine (DCS), a second line antibiotic used in the treatment of multidrug resistant Mycobacterium tuberculosis infections. We use doubly labeled 13C α-carbon-2H l-alanine to allow tracking of both alanine racemase and d-alanine:d-alanine ligase activity in M. tuberculosis challenged with DCS and reveal that d-alanine:d-alanine ligase is more strongly inhibited than alanine racemase at equivalent DCS concentrations. We also shed light on mechanisms surrounding d-Ala-mediated antagonism of DCS growth inhibition and provide evidence for a postantibiotic effect for this drug. Our results illustrate the potential of metabolomics in cellular drug-target engagement studies and consequently have broad implications in future drug development and target validation ventures.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Prosser GA,de Carvalho LP

doi

10.1021/ml400349n

subject

Has Abstract

pub_date

2013-12-12 00:00:00

pages

1233-1237

issue

12

issn

1948-5875

journal_volume

4

pub_type

杂志文章

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