The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an α-glucan pathway
Open accessAbstract
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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Cites
TM4: a free, open-source system for microarray data management and analysis
Saeed, A. I., Sharov, V., White, J., Li, J., Liang, W., Bhagabati, N., Braisted, J., Klapa, M., Currier, T., Thiagarajan, M., et al. (2003) · BioTechniques · doi:10.2144/03342mt01 · Cited by 4,837
Self-citationGenes required for mycobacterial growth defined by high density mutagenesis
Sassetti, C. M., Boyd, D. H., & Rubin, E. J. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03425.x · Cited by 2,544
Exploring genetic interactions and networks with yeast
Boone, C., Bussey, H., & Andrews, B. J. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2085 · Cited by 661
Cited by
Structure of mycobacterial maltokinase, the missing link in the essential GlgE-pathway
Fraga, J., Maranha, A., Mendes, V., Pereira, P. J. B., Empadinhas, N., & Macedo-Ribeiro, S. (2015) · Scientific Reports · doi:10.1038/srep08026 · Cited by 819
Probing the Mycobacterial Trehalome with Bioorthogonal Chemistry
Swarts, B. M., Holsclaw, C. M., Jewett, J. C., Alber, M., Fox, D. M., Siegrist, M. S., Leary, J. A., Kalscheuer, R., & Bertozzi, C. R. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3062419 · Cited by 184
Self-citationLee, J. J., Lee, S.-K., Song, N., Nathan, T. O., Swarts, B. M., Eum, S.-Y., Ehrt, S., Cho, S.-N., & Eoh, H. (2019) · Nature Communications · doi:10.1038/s41467-019-10975-7 · Cited by 122
Metabolic anticipation in Mycobacterium tuberculosis
Eoh, H., Wang, Z., Layre, E., Rath, P., Morris, R., Branch Moody, D., & Rhee, K. Y. (2017) · Nature Microbiology · doi:10.1038/nmicrobiol.2017.84 · Cited by 113
Puckett, S., Trujillo, C., Eoh, H., Marrero, J., Spencer, J., Jackson, M., Schnappinger, D., Rhee, K., & Ehrt, S. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004144 · Cited by 72
Metadata
- Authors
- Kalscheuer, R., Syson, K., Veeraraghavan, U., Weinrick, B., Biermann, K. E., Liu, Z., Sacchettini, J. C., Besra, G., Bornemann, S., & Jacobs, W. R.
- Venue
- Nature Chemical Biology
- Published
- 2010-03-21
- Volume
- 6
- Issue
- 5
- Pages
- 376-384
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2008402427
- Cited by
- 159
- References
- 3
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- green
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- Kalscheuer, R., Syson, K., Veeraraghavan, U., Weinrick, B., Biermann, K. E., Liu, Z., Sacchettini, J. C., Besra, G., Bornemann, S., & Jacobs, W. R. (2010). Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an α-glucan pathway. Nature Chemical Biology. https://doi.org/10.1038/nchembio.340
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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