, 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.
The wide spectra of colonizing microorganism, likewise Burkholderia pseudomallei, has been found in different habitats, and presenting distinct activity, as exerting physiological functions among plants, or as a pathogen for man, animals and also as a phytopathogen. A common disease of men and animals caused by B. pseudomallei, melioidosis, is a severe morbidity that usually culminates in the host death. Soil samples from different areas in the Amapá state, in northern Brazil, were screened for environmental microorganisms to assess potential antimicrobial activity aiming at biotechnological applications. Among the prospected microorganisms, B. pseudomallei was isolated from high humidity soils, mangrove, which is rich in organic materials, produced by the diversified local flora and fauna. The isolated B. pseudomallei was identified by its biochemical profile and growth characteristics. Molecular confirmation of B. pseudomallei phenotypic identification was achieved by PCR amplification of the 16 S ribosomal DNA. The sequencing of amplified products confirmed that the Amapá sample, and two other isolates from human infections in Ceará state, northeast Brazil, were B. pseudomallei, and sequence alignement to the same specie, MSHR146 strain from Australia, and clone YN01 from uncultured Burkholderia sp., deposited in the GenBank, exhibited close phylogenetic relationship among them. Until now, there is no report of B. pseudomallei related disease among human and animal populations in the Amapá state, despite the finding of B. pseudomallei in it, in an area of water buffalo ranching and flowing small rivers utilized by human populations.
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