Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an alpha-glucan pathway.
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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.
Kalscheuer, R., Syson, K., Veeraraghavan, U., Weinrick, B., Biermann, K. E., Liu, Z., ... Jacobs, W. R.
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Kalscheuer, Rainer||Syson, Karl||Veeraraghavan, Usha||Weinrick, Brian||Biermann, Karolin E||Liu, Zhen||Sacchettini, James C||Besra, Gurdyal||Bornemann, Stephen||Jacobs, William R
