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Status |
Public on Feb 24, 2010 |
Title |
Maltose-1-Phosphate Stress Stimulon in Mycobacterium tuberculosis |
Organism |
Mycobacterium tuberculosis |
Experiment type |
Expression profiling by array
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Summary |
New chemotherapeutics are urgently required to control the tuberculosis pandemic fueled by the emergence of multidrug- and extensively-drug-resistant Mycobacterium tuberculosis strains and the bacterium`s catastrophic alliance with HIV. Here we describe a novel trehalose-to-α-glucan pathway in M. tuberculosis comprising four enzymatic steps mediated by TreS, Pep2, GlgB, and GlgE, identified as an essential maltosyltransferase capable of utilizing maltose 1-phosphate. Using traditional and chemical reverse genetics, we show that GlgE inactivation causes rapid death of M. tuberculosis in vitro and in mice, through self-poisoning by maltose 1-phosphate accumulation driven by a self-amplifying feedback loop promoting pleiotropic phosphosugar-induced stress responses. Moreover, this α-glucan pathway exhibited a synthetic lethal interaction with the glucosyltransferase Rv3032 involved in biosynthesis of specialized α-glucan derivatives. The unique combination of gene essentiality within a synthetic lethal pathway validates GlgE as a new class of drug targets, revealing novel synergistic mechanisms to induce death in M. tuberculosis. Transcriptional profiling was performed to characterize the lethality induced by maltose 1-phosphate accumulation. Triplicate 10 mL cultures of the conditional lethal Mtb mutant strain H37Rv Delta treS Delta glgE (pMV361::treS) and of the vector control strain H37Rv Delta treS Delta glgE (pMV361) were grown in liquid culture to log-phase in the presence of 5 mM validamycin A (VA) to suppress M1P formation. Subsequently, cells were washed to remove the inhibitor; after 48 h of starvation for VA cultures were harvested.
Keywords: tuberculosis, trehalose, compound treatment design, genetic modification design, and stimulus or stress design
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Overall design |
Three biological replicates with one dye-flip
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Contributor(s) |
Weinrick B, Kalscheuer R |
Citation(s) |
- Kalscheuer R, Syson K, Veeraraghavan U, Weinrick B et al. Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an alpha-glucan pathway. Nat Chem Biol 2010 May;6(5):376-84. PMID: 20305657
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Submission date |
Oct 15, 2009 |
Last update date |
Nov 12, 2013 |
Contact name |
Brian Weinrick |
Organization name |
Trudeau Institute
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Street address |
154 Algonquin Avenue
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City |
Saranac Lake |
State/province |
NY |
ZIP/Postal code |
12983 |
Country |
USA |
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Platforms (1) |
GPL5774 |
JCVI PFGRC Mycobacterium tuberculosis 22K v4 array designed primarily based on strain H37Rv |
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Samples (3) |
GSM462141 |
Maltose-1-Phosphate Stress Stimulon in Mycobacterium tuberculosis Replicate 1 |
GSM462142 |
Maltose-1-Phosphate Stress Stimulon in Mycobacterium tuberculosis Replicate 2 |
GSM462143 |
Maltose-1-Phosphate Stress Stimulon in Mycobacterium tuberculosis Replicate 3 |
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Relations |
BioProject |
PRJNA120279 |
Supplementary file |
Size |
Download |
File type/resource |
GSE18575_RAW.tar |
3.2 Mb |
(http)(custom) |
TAR (of MEV) |
Processed data included within Sample table |
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