Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an α-glucan pathway

Rainer Kalscheuer, Karl Syson, Usha Veeraraghavan, Brian Weinrick, Karolin E. Biermann, Zhen Liu, James C. Sacchettini, Gurdyal Besra, Stephen Bornemann, William R. Jacobs

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

New chemotherapeutics are urgently required to control the tuberculosis pandemic. We describe a new pathway from trehalose to α-glucan in Mycobacterium tuberculosis comprising four enzymatic steps mediated by TreS, Pep2, GlgE (which has been identified as a maltosyltransferase that uses maltose 1-phosphate) and GlgB. Using traditional and chemical reverse genetics, we show that GlgE inactivation causes rapid death of M. tuberculosis in vitro and in mice through a self-poisoning accumulation of maltose 1-phosphate. Poisoning elicits pleiotropic phosphosugar-induced stress responses promoted by a self-amplifying feedback loop where trehalose-forming enzymes are upregulated. Moreover, the pathway from trehalose to α-glucan exhibited a synthetic lethal interaction with the glucosyltransferase Rv3032, which is involved in biosynthesis of polymethylated α-glucans, because key enzymes in each pathway could not be simultaneously inactivated. The unique combination of maltose 1-phosphate toxicity and gene essentiality within a synthetic lethal pathway validates GlgE as a distinct potential drug target that exploits new synergistic mechanisms to induce death in M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)376-384
Number of pages9
JournalNature Chemical Biology
Volume6
Issue number5
DOIs
StatePublished - May 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kalscheuer, R., Syson, K., Veeraraghavan, U., Weinrick, B., Biermann, K. E., Liu, Z., Sacchettini, J. C., Besra, G., Bornemann, S., & Jacobs, W. R. (2010). Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an α-glucan pathway. Nature Chemical Biology, 6(5), 376-384. https://doi.org/10.1038/nchembio.340