Malleilactone is a Burkholderia pseudomallei virulence factor regulated by antibiotics and quorum sensing

Jennifer R. Klaus, Jacqueline Deay, Benjamin Neuenswander, Wyatt Hursh, Zhe Gao, Tiffany Bouddhara, Todd D. Williams, Justin Douglas, Kyle Monize, Patricia Martins, Charlotte Majerczyk, Mohammad R. Seyedsayamdost, Blake R. Peterson, Mario Rivera, Josephine R. Chandler

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Burkholderia pseudomallei, the causative agent of melioidosis, encodes almost a dozen predicted polyketide (PK) biosynthetic gene clusters. Many of these are regulated by LuxR-I-type acyl-homoserine (AHL) quorum-sensing systems. One of the PK gene clusters, the mal gene cluster, is conserved in the close relative Burkholderia thailandensis. The B. thailandensis mal genes code for the cytotoxin malleilactone and are regulated by a genetically linked LuxR-type transcription factor, MalR. Although AHLs typically interact with LuxR-type proteins to modulate gene transcription, the B. thailandensis MalR does not appear to be an AHL receptor. Here, we characterize the mal genes and MalR in B. pseudomallei. We use chemical analyses to demonstrate that the B. pseudomallei mal genes code for malleilactone. Our results show that MalR and the mal genes contribute to the ability of B. pseudomallei to kill Caenorhabditis elegans. In B. thailandensis, antibiotics like trimethoprim can activate MalR by driving transcription of the mal genes, and we demonstrate that some of the same antibiotics induce expression of B. pseudomallei malR. We also demonstrate that B. pseudomallei MalR does not respond directly to AHLs. Our results suggest that MalR is indirectly repressed by AHLs, possibly through a repressor, ScmR. We further show that malleilactone is a B. pseudomallei virulence factor and provide the foundation for understanding how malleilactone contributes to the pathology of melioidosis infections.

Original languageEnglish (US)
Article numbere00008-18
JournalJournal of bacteriology
Volume200
Issue number14
DOIs
StatePublished - Jul 1 2018

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Keywords

  • Burkholderia
  • Polyketide
  • Quorum sensing

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    Klaus, J. R., Deay, J., Neuenswander, B., Hursh, W., Gao, Z., Bouddhara, T., Williams, T. D., Douglas, J., Monize, K., Martins, P., Majerczyk, C., Seyedsayamdost, M. R., Peterson, B. R., Rivera, M., & Chandler, J. R. (2018). Malleilactone is a Burkholderia pseudomallei virulence factor regulated by antibiotics and quorum sensing. Journal of bacteriology, 200(14), [e00008-18]. https://doi.org/10.1128/JB.00008-18