The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis
Open accessAbstract
SQ109, a 1,2-diamine related to ethambutol, is currently in clinical trials for the treatment of tuberculosis, but its mode of action remains unclear. Here, we demonstrate that SQ109 disrupts cell wall assembly, as evidenced by macromolecular incorporation assays and ultrastructural analyses. SQ109 interferes with the assembly of mycolic acids into the cell wall core of Mycobacterium tuberculosis , as bacilli exposed to SQ109 show immediate inhibition of trehalose dimycolate (TDM) production and fail to attach mycolates to the cell wall arabinogalactan. These effects were not due to inhibition of mycolate synthesis, since total mycolate levels were unaffected, but instead resulted in the accumulation of trehalose monomycolate (TMM), the precursor of TDM and cell wall mycolates. In vitro assays using purified enzymes showed that this was not due to inhibition of the secreted Ag85 mycolyltransferases. We were unable to achieve spontaneous generation of SQ109-resistant mutants; however, analogs of this compound that resulted in similar shutdown of TDM synthesis with concomitant TMM accumulation were used to spontaneously generate resistant mutants that were also cross-resistant to SQ109. Whole-genome sequencing of these mutants showed that these all had mutations in the essential mmpL3 gene, which encodes a transmembrane transporter. Our results suggest that MmpL3 is the target of SQ109 and that MmpL3 is a transporter of mycobacterial TMM.
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The Sequence Alignment/Map format and SAMtools
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Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis
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Uptake of unnatural trehalose analogs as a reporter for Mycobacterium tuberculosis
Backus, K. M., Boshoff, H. I., Barry, C. S., Boutureira, O., Patel, M. K., D'Hooge, F., Lee, S. S., Via, L. E., Tahlan, K., Barry, C. E., et al. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.539 · Cited by 237
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Advances in the development of new tuberculosis drugs and treatment regimens
Zumla, A., Nahid, P., & Cole, S. T. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4001 · Cited by 893
DeJesus, M. A., Gerrick, E. R., Xu, W., Park, S. W., Long, J. E., Boutte, C. C., Rubin, E. J., Schnappinger, D., Ehrt, S., Fortune, S. M., et al. (2017) · mBio · doi:10.1128/mbio.02133-16 · Cited by 668
Mycolic Acids: Structures, Biosynthesis, and Beyond
Marrakchi, H., Lanéelle, M.-A., & Daffé, M. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.11.011 · Cited by 623
Discovery of a Siderophore Export System Essential for Virulence of Mycobacterium tuberculosis
Wells, R. M., Jones, C. M., Xi, Z., Speer, A., Danilchanka, O., Doornbos, K. S., Sun, P., Wu, F., Tian, C., & Niederweis, M. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003120 · Cited by 267
Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target
Zhang, B., Li, J., Yang, X., Wu, L., Zhang, J., Yang, Y., Zhao, Y., Zhang, L., Yang, X., Yang, X., et al. (2019) · Cell · doi:10.1016/j.cell.2019.01.003 · Cited by 263
Metadata
- Authors
- Tahlan, K., Wilson, R., Kastrinsky, D. B., Arora, K., Nair, V., Fischer, E., Barnes, S. W., Walker, J. R., Alland, D., Barry, C. E., & Boshoff, H. I.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2012-04
- Volume
- 56
- Issue
- 4
- Pages
- 1797-1809
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- OpenAlex
- W2155375392
- Cited by
- 504
- References
- 7
- FWCI
- 27.32
- Type
- journal article
- Language
- en
- Open access
- green
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- Tahlan, K., Wilson, R., Kastrinsky, D. B., Arora, K., Nair, V., Fischer, E., Barnes, S. W., Walker, J. R., Alland, D., Barry, C. E., & Boshoff, H. I. (2012). SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy. https://doi.org/10.1128/aac.05708-11
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