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

TitleMalleilactone Is a Burkholderia pseudomallei Virulence Factor Regulated by Antibiotics and Quorum Sensing.
Publication TypeJournal Article
Year of Publication2018
AuthorsKlaus, JR, Deay, J, Neuenswander, B, Hursh, W, Gao, Z, Bouddhara, T, Williams, TD, Douglas, J, Monize, K, Martins, P, Majerczyk, C, Seyedsayamdost, MR, Peterson, BR, Rivera, M, Chandler, JR
JournalJ Bacteriol
Volume200
Issue14
Date Published2018 07 15
ISSN1098-5530
KeywordsA549 Cells, Animals, Anti-Bacterial Agents, Bacterial Proteins, Burkholderia pseudomallei, Caenorhabditis elegans, Gene Expression Regulation, Bacterial, Humans, Jurkat Cells, Lactones, Quorum Sensing, Virulence, Virulence Factors
Abstract

<p>, 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 gene cluster, is conserved in the close relative The 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 MalR does not appear to be an AHL receptor. Here, we characterize the genes and MalR in We use chemical analyses to demonstrate that the genes code for malleilactone. Our results show that MalR and the genes contribute to the ability of to kill In , antibiotics like trimethoprim can activate MalR by driving transcription of the genes, and we demonstrate that some of the same antibiotics induce expression of We also demonstrate that 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 virulence factor and provide the foundation for understanding how malleilactone contributes to the pathology of melioidosis infections. 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 , which causes the often-fatal human disease melioidosis. Using knowledge gained by studies in the close relative , we show that one of the polyketide biosynthetic clusters produces a cytotoxic polyketide, malleilactone. Malleilactone contributes to virulence in a 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.</p>

DOI10.1128/JB.00008-18
Alternate JournalJ Bacteriol
PubMed ID29735757
PubMed Central IDPMC6018353
Grant ListR01 CA211720 / CA / NCI NIH HHS / United States
S10 RR024664 / RR / NCRR NIH HHS / United States
R01 AI125529 / AI / NIAID NIH HHS / United States
P20 GM103638 / GM / NIGMS NIH HHS / United States
R24 GM111385 / GM / NIGMS NIH HHS / United States
K12 GM063651 / GM / NIGMS NIH HHS / United States