Malleilactone is a virulence factor regulated by antibiotics and quorum sensing.

TitleMalleilactone is a 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
Date Published2018 May 07
ISSN1098-5530
Abstract

, 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 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 some of the same antibiotics induce expression of We also demonstrate MalR does not respond to AHLs directly. Our results suggest 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 potentially important contributors to pathogenesis during infection. We are interested in the polyketide gene clusters encoded by which causes the often fatal human disease melioidosis. Using knowledge gained by studies in the close relative, we show 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.

DOI10.1128/JB.00008-18
Alternate JournalJ. Bacteriol.
PubMed ID29735757