A High-Throughput Screen against Pantothenate Synthetase

The enzyme pantothenate synthetase, PanC, is an attractive drug target in Mycobacterium tuberculosis. It is essential for the in vitro growth of M. tuberculosis and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identi...

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Bibliographic Details
Published in:PloS one 2013-11, Vol.8 (11), p.e72786
Main Authors: Kumar, Anuradha, Casey, Allen, Odingo, Joshua, Kesicki, Edward A, Abrahams, Garth, Vieth, Michal, Masquelin, Thierry, Mizrahi, Valerie, Hipskind, Philip A, Sherman, David R, Parish, Tanya
Format: Article
Language:English
Subjects:
Biphenyl (Compound)
Health aspects
Ligases
Organic acids
Recombinant proteins
Tuberculosis
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Summary:The enzyme pantothenate synthetase, PanC, is an attractive drug target in Mycobacterium tuberculosis. It is essential for the in vitro growth of M. tuberculosis and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identify inhibitors of PanC, optimized it for high-throughput screening, and tested a large and diverse library of compounds for activity. Two compounds belonging to the same chemical class of 3-biphenyl-4- cyanopyrrole-2-carboxylic acids had activity against the purified recombinant protein, and also inhibited growth of live M. tuberculosis in manner consistent with PanC inhibition. Thus we have identified a new class of PanC inhibitors with whole cell activity that can be further developed.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0072786