Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an α-glucan pathway Academic Article uri icon

abstract

  • New chemotherapeutics are urgently required to control the tuberculosis pandemic. We describe a new pathway from trehalose to alpha-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 alpha-glucan exhibited a synthetic lethal interaction with the glucosyltransferase Rv3032, which is involved in biosynthesis of polymethylated alpha-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.

altmetric score

  • 12.456

author list (cited authors)

  • Kalscheuer, R., Syson, K., Veeraraghavan, U., Weinrick, B., Biermann, K. E., Liu, Z., ... Jacobs, W. R.

citation count

  • 113

complete list of authors

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

publication date

  • March 2010