Dataset Information

Mapping the Trimethoprim-Induced Secondary Metabolome of Burkholderia thailandensis.

ABSTRACT: While bacterial genomes typically contain numerous secondary metabolite biosynthetic gene clusters, only a small fraction of these are expressed at any given time. The remaining majority is inactive or silent, and methods that awaken them would greatly expand our repertoire of bioactive molecules. We recently devised a new approach for identifying inducers of silent gene clusters and proposed that the clinical antibiotic trimethoprim acted as a global activator of secondary metabolism in Burkholderia thailandensis. Herein, we report that trimethoprim triggers the production of over 100 compounds that are not observed under standard growth conditions, thus drastically modulating the secondary metabolic output of B. thailandensis. Using MS/MS networking and NMR, we assign structures to ?40 compounds, including a group of new molecules, which we call acybolins. With methods at hand for activation of silent gene clusters and rapid identification of small molecules, the hidden secondary metabolomes of bacteria can be interrogated.

SUBMITTER: Okada BK

PROVIDER: S-EPMC6786267 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Mapping the Trimethoprim-Induced Secondary Metabolome of Burkholderia thailandensis.

Okada Bethany K BK Wu Yihan Y Mao Dainan D Bushin Leah B LB Seyedsayamdost Mohammad R MR

ACS chemical biology 20160701 8

While bacterial genomes typically contain numerous secondary metabolite biosynthetic gene clusters, only a small fraction of these are expressed at any given time. The remaining majority is inactive or silent, and methods that awaken them would greatly expand our repertoire of bioactive molecules. We recently devised a new approach for identifying inducers of silent gene clusters and proposed that the clinical antibiotic trimethoprim acted as a global activator of secondary metabolism in Burkhol ...[more]

PMID: 27367535

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Project description:Burkholderia thailandensis is a soil saprophyte that is closely related to the pathogen Burkholderia pseudomallei, the etiological agent of melioidosis in humans. The environmental niches and infection sites occupied by these bacteria are thought to contain only limited concentrations of oxygen, where they can generate energy via denitrification. However, knowledge of the underlying molecular basis of the denitrification pathway in these bacteria is scarce. In this study, we employed a transposon sequencing (Tn-Seq) approach to identify genes conferring a fitness benefit for anaerobic growth of B. thailandensis Of the 180 determinants identified, several genes were shown to be required for growth under denitrifying conditions: the nitrate reductase operon narIJHGK2K1, the aniA gene encoding a previously unknown nitrite reductase, and the petABC genes encoding a cytochrome bc1, as well as three novel regulators that control denitrification. Our Tn-Seq data allowed us to reconstruct the entire denitrification pathway of B. thailandensis and shed light on its regulation. Analyses of growth behaviors combined with measurements of denitrification metabolites of various mutants revealed that nitrate reduction provides sufficient energy for anaerobic growth, an important finding in light of the fact that some pathogenic Burkholderia species can use nitrate as a terminal electron acceptor but are unable to complete denitrification. Finally, we demonstrated that a nitrous oxide reductase mutant is not affected for anaerobic growth but is defective in biofilm formation and accumulates N2O, which may play a role in the dispersal of B. thailandensis biofilms.IMPORTANCEBurkholderia thailandensis is a soil-dwelling saprophyte that is often used as surrogate of the closely related pathogen Burkholderia pseudomallei, the causative agent of melioidosis and a classified biowarfare agent. Both organisms are adapted to grow under oxygen-limited conditions in rice fields by generating energy through denitrification. Microoxic growth of B. pseudomallei is also considered essential for human infections. Here, we have used a Tn-Seq approach to identify the genes encoding the enzymes and regulators required for growth under denitrifying conditions. We show that a mutant that is defective in the conversion of N2O to N2, the last step in the denitrification process, is unaffected in microoxic growth but is severely impaired in biofilm formation, suggesting that N2O may play a role in biofilm dispersal. Our study identified novel targets for the development of therapeutic agents to treat meliodiosis.

Dataset Information

Mapping the Trimethoprim-Induced Secondary Metabolome of Burkholderia thailandensis.

Publications

Mapping the Trimethoprim-Induced Secondary Metabolome of Burkholderia thailandensis.

Similar Datasets

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