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Series GSE18575 Query DataSets for GSE18575
Status Public on Feb 24, 2010
Title Maltose-1-Phosphate Stress Stimulon in Mycobacterium tuberculosis
Organism Mycobacterium tuberculosis
Experiment type Expression profiling by array
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
 
Overall design Three biological replicates with one dye-flip
 
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
Submission date Oct 15, 2009
Last update date Nov 12, 2013
Contact name Brian Weinrick
Organization name Trudeau Institute
Street address 154 Algonquin Avenue
City Saranac Lake
State/province NY
ZIP/Postal code 12983
Country USA
 
Platforms (1)
GPL5774 JCVI PFGRC Mycobacterium tuberculosis 22K v4 array designed primarily based on strain H37Rv
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
Relations
BioProject PRJNA120279

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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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