A high-throughput screen against pantothenate synthetase (PanC) identifies 3-biphenyl-4-cyanopyrrole-2-carboxylic acids as a new class of inhibitor with activity against Mycobacterium tuberculosis

PLoS One. 2013 Nov 7;8(11):e72786. doi: 10.1371/journal.pone.0072786. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Microbial Viability / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Peptide Synthases / antagonists & inhibitors*
  • Peptide Synthases / chemistry
  • Peptide Synthases / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Tuberculosis / drug therapy*
  • Tuberculosis / enzymology
  • Vero Cells

Substances

  • Bacterial Proteins
  • Enzyme Inhibitors
  • Recombinant Proteins
  • Peptide Synthases
  • pantothenate synthetase

Grants and funding

This work was funded by the Lilly TB Drug Discovery Initiative (http://www.tbdrugdiscovery.org/). Funding for the Lilly TB Drug Discovery Initiative was provided by Eli Lilly and Company. The following authors are employed by Eli Lilly and Company and made the contributions to the paper noted in the authors' contribution - Michal Vieth, Thierry Masquelin, Philip A. Hipskind.