Malleilactone Is a Burkholderia pseudomallei Virulence Factor Regulated by Antibiotics and Quorum Sensing.

Autor:	Klaus JR; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Deay J; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Neuenswander B; Chemical Methodologies and Library Development Legacy, University of Kansas, Lawrence, Kansas, USA., Hursh W; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Gao Z; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA., Bouddhara T; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Williams TD; Mass Spectrometry and Analytical Proteomics Laboratory, University of Kansas, Lawrence, Kansas, USA., Douglas J; Nuclear Magnetic Resonance Core Laboratory, University of Kansas, Lawrence, Kansas, USA., Monize K; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Martins P; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Majerczyk C; Department of Microbiology, University of Washington, Seattle, Washington, USA., Seyedsayamdost MR; Department of Chemistry, Princeton University, Princeton, New Jersey, USA., Peterson BR; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA., Rivera M; Department of Chemistry, University of Kansas, Lawrence, Kansas, USA., Chandler JR; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA jrchandler@ku.edu.
Jazyk:	angličtina
Zdroj:	Journal of bacteriology [J Bacteriol] 2018 Jun 25; Vol. 200 (14). Date of Electronic Publication: 2018 Jun 25 (Print Publication: 2018).
DOI:	10.1128/JB.00008-18
Abstrakt:	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. IMPORTANCE Many bacterially produced polyketides are cytotoxic to mammalian cells and are potentially important contributors to pathogenesis during infection. We are interested in the polyketide gene clusters present in Burkholderia pseudomallei , which causes the often-fatal human disease melioidosis. Using knowledge gained by studies in the close relative Burkholderia thailandensis , we show that one of the B. pseudomallei polyketide biosynthetic clusters produces a cytotoxic polyketide, malleilactone. Malleilactone contributes to B. pseudomallei virulence in a Caenorhabditis elegans infection model and is regulated by an orphan LuxR family quorum-sensing transcription factor, MalR. Our studies demonstrate that malleilactone biosynthesis or MalR could be new targets for developing therapeutics to treat melioidosis. (Copyright © 2018 American Society for Microbiology.)
Databáze:	MEDLINE
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