Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane

Anna E. Grzegorzewicz, Ha Pham, Vijay A.K.B. Gundi, Michael S. Scherman, Elton J. North, Tamara Hess, Victoria Jones, Veronica Gruppo, Sarah E.M. Born, Jana Korduláková, Sivagami Sundaram Chavadi, Christophe Morisseau, Anne J. Lenaerts, Richard E. Lee, Michael R. McNeil, Mary Jackson

Research output: Contribution to journalArticle

234 Scopus citations

Abstract

New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.

Original languageEnglish (US)
Pages (from-to)334-341
Number of pages8
JournalNature Chemical Biology
Volume8
Issue number4
DOIs
StatePublished - Apr 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Grzegorzewicz, A. E., Pham, H., Gundi, V. A. K. B., Scherman, M. S., North, E. J., Hess, T., Jones, V., Gruppo, V., Born, S. E. M., Korduláková, J., Chavadi, S. S., Morisseau, C., Lenaerts, A. J., Lee, R. E., McNeil, M. R., & Jackson, M. (2012). Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nature Chemical Biology, 8(4), 334-341. https://doi.org/10.1038/nchembio.794