Genomics‐Driven Discovery of Burkholderic Acid, a Noncanonical, Cryptic Polyketide from Human Pathogenic <i>Burkholderia</i> Species

Franke, Jakob; Ishida, Keishi; Hertweck, Christian

doi:10.1002/ange.201205566

Cited by 39 publications

(28 citation statements)

References 48 publications

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“…It was noticed that induction of malleilactone by 6 or 7 resulted in the appearance of two additional malleilactones that were not reported in previous studies (19,20 365.1964). Multiple attempts to purify the second analog were unsuccessful due to the instability of this group of metabolites (20). Isolation and structural elucidation by multidimensional NMR for the first compound revealed hydroxy-malleilactone (2, Fig.…”

Section: 1909 [M+h]mentioning

confidence: 75%

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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: 1909 [M+h]mentioning

confidence: 75%

“…Within the Pseudomallei group pathogens--which include E264, Burkholderia mallei, and Burkholderia pseudomallei--malleilactone is a virulence factor required for nematode infections, and its structure was recently determined (1, Fig. 1A) (18)(19)(20). However, the elicitors that lead to activation of this silent virulence factor are not known.…”

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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“…Connecting these natural products to the genes that encode them is revolutionizing their study, enabling genome sequence data to guide the discovery of new molecules (Bergmann et al, 2007;Challis, 2008;Franke et al, 2012;Freeman et al, 2012;Kersten et al, 2011;Laureti et al, 2011;Lautru et al, 2005;Letzel et al, 2013;Nguyen et al, 2008;Oliynyk et al, 2007;Schneiker et al, 2007;Walsh and Fischbach, 2010;Winter et al, 2011). The thousands of prokaryotic genomes in sequence databases provide an opportunity to generalize this approach through the identification of biosynthetic gene clusters (BGCs): sets of physically clustered genes that encode the biosynthetic enzymes for a natural product pathway.…”

Section: Introductionmentioning

confidence: 99%

Galaxy masses

et al. 2014

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“…1) (18). By using a promoter insertion strategy, the Brady and Hertweck groups were able to induce and structurally elucidate malleilactone, the valence tautomer of which is referred to as burkholderic acid (7) (15,16). The Brady group further showed that the mal cluster is required for toxicity in Caenorhabditis elegans, suggesting that malleilactone is a silent virulence factor against worms.…”

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confidence: 99%

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

Mao

Bushin

Moon

et al. 2017

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

140

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Bacteria produce a diverse array of secondary metabolites that have been invaluable in the clinic and in research. These metabolites are synthesized by dedicated biosynthetic gene clusters (BGCs), which assemble architecturally complex molecules from simple building blocks. The majority of BGCs in a given bacterium are not expressed under normal laboratory growth conditions, and our understanding of how they are silenced is in its infancy. Here, we have addressed this question in the Gram-negative model bacterium Burkholderia thailandensis E264 using genetic, transcriptomic, metabolomic, and chemical approaches. We report that a previously unknown, quorum-sensing-controlled LysR-type transcriptional regulator, which we name ScmR (for secondary metabolite regulator), serves as a global gatekeeper of secondary metabolism and a repressor of numerous BGCs. Transcriptionally, we find that 13 of the 20 BGCs in B. thailandensis are significantly (threefold or more) upor down-regulated in a scmR deletion mutant (ΔscmR). Metabolically, the ΔscmR strain displays a hyperactive phenotype relative to wild type and overproduces a number of compound families by 18-to 210-fold, including the silent virulence factor malleilactone. Accordingly, the ΔscmR mutant is hypervirulent both in vitro and in a Caenorhabditis elegans model in vivo. Aside from secondary metabolism, ScmR also represses biofilm formation and transcriptionally activates ATP synthesis and stress response. Collectively, our data suggest that ScmR is a pleiotropic regulator of secondary metabolism, virulence, biofilm formation, and other stationary phase processes. A model for how the interplay of ScmR with pathwayspecific transcriptional regulators coordinately silences virulence factor production is proposed.biosynthetic gene clusters | natural products | Burkholderia thailandensis | regulation | virulence

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Genomics‐Driven Discovery of Burkholderic Acid, a Noncanonical, Cryptic Polyketide from Human Pathogenic Burkholderia Species

Cited by 39 publications

References 48 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

Galaxy masses

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

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