TY - JOUR
T1 - Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an α-glucan pathway
AU - Kalscheuer, Rainer
AU - Syson, Karl
AU - Veeraraghavan, Usha
AU - Weinrick, Brian
AU - Biermann, Karolin E.
AU - Liu, Zhen
AU - Sacchettini, James C.
AU - Besra, Gurdyal
AU - Bornemann, Stephen
AU - Jacobs, William R.
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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.
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U2 - 10.1038/nchembio.340
DO - 10.1038/nchembio.340
M3 - Article
C2 - 20305657
AN - SCOPUS:77951296166
VL - 6
SP - 376
EP - 384
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 5
ER -