Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis

Regina Wilson, Pradeep Kumar, Vijay Parashar, Catherine Vilchèze, Romain Veyron-Churlet, Joel S. Freundlich, S. Whitney Barnes, John R. Walker, Michael J. Szymonifka, Emily Marchiano, Shubhada Shenai, Roberto Colangeli, William R. Jacobs, Matthew B. Neiditch, Laurent Kremer, David Alland

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72 Scopus citations

Abstract

We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis by the previously uncharacterized mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser55 site in Pks13 conferred TP resistance in M. tuberculosis. Overexpression of wild-type Pks13 resulted in TP resistance, and overexpression of the Pks13 F79S mutant conferred high resistance. In vitro, TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type M. tuberculosis, but it did so to a much lesser extent in TP-resistant M. tuberculosis. TP treatment was bactericidal and equivalent to treatment with the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment resulted in sterilizing activity. Computational docking identified a possible TP-binding groove within the Pks13 acyl carrier protein domain. This study confirms that M. tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.

Original languageEnglish (US)
Pages (from-to)499-506
Number of pages8
JournalNature Chemical Biology
Volume9
Issue number8
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Wilson, R., Kumar, P., Parashar, V., Vilchèze, C., Veyron-Churlet, R., Freundlich, J. S., Barnes, S. W., Walker, J. R., Szymonifka, M. J., Marchiano, E., Shenai, S., Colangeli, R., Jacobs, W. R., Neiditch, M. B., Kremer, L., & Alland, D. (2013). Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nature Chemical Biology, 9(8), 499-506. https://doi.org/10.1038/nchembio.1277