Quorum-Sensing Control of Antibiotic Synthesis in
            <i>Burkholderia thailandensis</i>

Duerkop, Breck A.; Varga, John J.; Chandler, Josephine R.; Peterson, S. Brook; Herman, Jake P.; Churchill, Mair E. A.; Parsek, Matthew R.; Nierman, William C.; Greenberg, E. Peter

doi:10.1128/jb.00200-09

Cited by 132 publications

(164 citation statements)

References 74 publications

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“…malL-lacZ is not expressed under standard growth conditions and served as a negative control. A lacZ reporter in btaK, which is quorum-sensing-regulated and expressed at high cell densities, provided a positive control (Methods) (21)(22)(23). A number of growth parameters, including temperature, growth media, agitation rates, total volume, and initial inoculum were assessed and provided an optimized, robust screening assay with a Z′ value of 0.51 in a 384-well format (SI Appendix, Table S1).…”

Section: Resultsmentioning

confidence: 99%

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

Seyedsayamdost

2014

Proc. Natl. Acad. Sci. U.S.A.

240

235

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Over the past decade, bacterial genome sequences have revealed an immense reservoir of biosynthetic gene clusters, sets of contiguous genes that have the potential to produce drugs or drug-like molecules. However, the majority of these gene clusters appear to be inactive for unknown reasons prompting terms such as "cryptic" or "silent" to describe them. Because natural products have been a major source of therapeutic molecules, methods that rationally activate these silent clusters would have a profound impact on drug discovery. Herein, a new strategy is outlined for awakening silent gene clusters using small molecule elicitors. In this method, a genetic reporter construct affords a facile read-out for activation of the silent cluster of interest, while high-throughput screening of small molecule libraries provides potential inducers. This approach was applied to two cryptic gene clusters in the pathogenic model Burkholderia thailandensis. The results not only demonstrate a prominent activation of these two clusters, but also reveal that the majority of elicitors are themselves antibiotics, most in common clinical use. Antibiotics, which kill B. thailandensis at high concentrations, act as inducers of secondary metabolism at low concentrations. One of these antibiotics, trimethoprim, served as a global activator of secondary metabolism by inducing at least five biosynthetic pathways. Further application of this strategy promises to uncover the regulatory networks that activate silent gene clusters while at the same time providing access to the vast array of cryptic molecules found in bacteria.natural products discovery | cryptic metabolites | malleilactone

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Section: Resultsmentioning

confidence: 99%

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

Seyedsayamdost

2014

Proc. Natl. Acad. Sci. U.S.A.

240

235

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“…Because of the signal diffusibility, AHLs must reach a critical environmental concentration before they cause changes in gene expression. It is common that the AHL synthase gene is among the genes activated, creating a positive feedback loop that results in increased production of signal (Engebrecht et al, 1983;Seed et al, 1995;Latifi et al, 1996;Duerkop et al, 2009;Stauff and Bassler, 2011). Thus, AHL signaling can coordinate population-wide changes in a celldensity-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Acyl-homoserine lactone-dependent eavesdropping promotes competition in a laboratory co-culture model

et al. 2012

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Many Proteobacteria use acyl-homoserine lactone (AHL)-mediated quorum sensing to activate the production of antibiotics at high cell density. Extracellular factors like antibiotics can be considered public goods shared by individuals within a group. Quorum-sensing control of antibiotic production may be important for protecting a niche or competing for limited resources in mixed bacterial communities. To begin to investigate the role of quorum sensing in interspecies competition, we developed a dual-species co-culture model using the soil saprophytes Burkholderia thailandensis (Bt) and Chromobacterium violaceum (Cv). These bacteria require quorum sensing to activate the production of antimicrobial factors that inhibit growth of the other species. We demonstrate that quorum-sensing-dependent antimicrobials can provide a competitive advantage to either Bt or Cv by inhibiting growth of the other species in co-culture. Although the quorum-sensing signals differ for each species, we show that the promiscuous signal receptor encoded by Cv can sense signals produced by Bt, and that this ability to eavesdrop on Bt can provide Cv an advantage in certain situations. We use an in silico approach to investigate the effect of eavesdropping in competition, and show conditions where early activation of antibiotic production resulting from eavesdropping can promote competitiveness. Our work supports the idea that quorum sensing is important for interspecies competition and that promiscuous signal receptors allow eavesdropping on competitors in mixed microbial habitats.

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“…B. mallei has retained QS-1 and QS-3, but not QS-2. The B. thailandensis QS-1 circuit consists of the BtaI1-BtaR1 pair and the signal N-octanoyl homoserine lactone (C 8 -HSL) (6, 7), QS-2 consists of BtaI2-BtaR2 and N-3-hydroxy-decanoyl homoserine lactone (3OHC 10 -HSL) (6,8), and QS-3 consists of BtaI3-BtaR3 and N-3-hydroxy-octanoyl homoserine lactone (3OHC 8 -HSL) (6,7). Additionally, each member of the Bptm group contains two orphan LuxR homologs (LuxR homologs without a cognate LuxI homolog).…”

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confidence: 99%

Global Analysis of the Burkholderia thailandensis Quorum Sensing-Controlled Regulon

et al. 2014

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c Burkholderia thailandensis contains three acyl-homoserine lactone quorum sensing circuits and has two additional LuxR homologs. To identify B. thailandensis quorum sensing-controlled genes, we carried out transcriptome sequencing (RNA-seq) analyses of quorum sensing mutants and their parent. The analyses were grounded in the fact that we identified genes coding for factors shown previously to be regulated by quorum sensing among a larger set of quorum-controlled genes. We also found that genes coding for contact-dependent inhibition were induced by quorum sensing and confirmed that specific quorum sensing mutants had a contact-dependent inhibition defect. Additional quorum-controlled genes included those for the production of numerous secondary metabolites, an uncharacterized exopolysaccharide, and a predicted chitin-binding protein. This study provides insights into the roles of the three quorum sensing circuits in the saprophytic lifestyle of B. thailandensis, and it provides a foundation on which to build an understanding of the roles of quorum sensing in the biology of B. thailandensis and the closely related pathogenic Burkholderia pseudomallei and Burkholderia mallei.

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Quorum-Sensing Control of Antibiotic Synthesis in Burkholderia thailandensis

Cited by 132 publications

References 74 publications

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

Acyl-homoserine lactone-dependent eavesdropping promotes competition in a laboratory co-culture model

Global Analysis of the Burkholderia thailandensis Quorum Sensing-Controlled Regulon

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