Projects per year
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.
Original language | English |
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Pages (from-to) | 376-384 |
Number of pages | 9 |
Journal | Nature Chemical Biology |
Volume | 6 |
Issue number | 5 |
DOIs | |
Publication status | Published - 1 May 2010 |
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Dive into the research topics of 'Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an alpha-glucan pathway'. Together they form a unique fingerprint.Projects
- 2 Finished
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Mycobacterium tuberculosis capsular alpha-glucan biosynthesis and characterisation of host-pathogen
Besra, D., Bhatt, A. & Lammas, T.
1/09/10 → 31/08/13
Project: Research Councils
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MAGPIE Project: The Structure and Assembly of the Mycobacterial Cell Envelope
Besra, D., Lammas, T. & Minnikin, D.
1/02/06 → 31/01/11
Project: Research Councils