Induced Biosynthesis of Cryptic Polyketide Metabolites in a Burkholderia thailandensis Quorum Sensing Mutant

Ishida, Keishi; Lincke, Thorger; Behnken, Swantje; Hertweck, Christian

doi:10.1021/ja105003g

Cited by 76 publications

(72 citation statements)

References 26 publications

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“…46 Expression of genes encoding proteins involved in malleilactone biosynthesis ( BTH_II2084-2099 ) is also under control of an orphan LuxR (BtaR4) that is encoded by BTH_II2087 and renamed MalR. 47 Malleilactone promotes virulence, as evidenced by prolonged survival of Caenorhabditis elegans fed B. thailandensis lacking an essential malleilactone biosynthesis gene.…”

Section: Resultsmentioning

confidence: 99%

Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis

et al. 2017

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Many bacteria encode biosynthetic proteins that produce a vast array of natural products. These compounds are often synthesized during host invasion as they function as virulence factors. In addition, such secondary metabolites have yielded numerous molecular scaffolds with pharmaceutical and clinical importance. The gene clusters that encode proteins responsible for synthesis of these compounds are typically silenced or “cryptic” under laboratory growth conditions, hampering discovery of novel lead compounds. We report here that MftR is a global repressor of secondary metabolite synthesis in Burkholderia thailandensis and that urate functions as a physiologically relevant inducer of gene expression. Biosynthetic gene clusters under MftR control include those associated with production of the antimicrobial bactobolins, the iron siderophore malleobactin, and the virulence factor malleilactone. MftR also controls additional genes associated with survival in a host environment, such as genes encoding components of the type III secretion system (T3SS) and proteins linked to anaerobic respiration. This observation not only has implications for understanding activation of gene regulatory networks during host invasion, but it also paves the way for isolation of novel therapeutic leads.

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Section: Resultsmentioning

confidence: 99%

Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis

et al. 2017

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“…For example, cloning out the large ATP-binding LuxR-type (LAL) regulatory gene and reintroducing it under control of a constitutive ermE*p led to identification of four novel, 51-membered, glycosylated macrolides stambomycins A–D (14) with activity against human cancer lines in Streptomyces ambofaciens ATCC23877 (Laureti et al, 2011). Not all regulatory elements are inducers of secondary metabolism, as was observed when mutagenic inactivation of the quorum-sensing regulator in Burkholderia thailandensis led to activation of a cryptic cluster encoding a novel polyketide metabolite, thailandamide lactone (Ishida et al, 2010). …”

Section: Activating Silent Pathways Through Host and Cluster Engineeringmentioning

confidence: 99%

Mining the Metabiome: Identifying Novel Natural Products from Microbial Communities

Milshteyn

Schneider

Brady

2014

Chemistry & Biology

164

144

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Summary Microbial-derived natural products provide the foundation for most of the chemotherapeutic arsenal available to contemporary medicine. In the face of a dwindling pipeline of new lead structures identified by traditional culturing techniques and an increasing need for new therapeutics, surveys of microbial biosynthetic diversity across environmental metabiomes have revealed enormous reservoirs of as yet untapped natural products chemistry. In this review we touch on the historical context of microbial natural product discovery and discuss innovations and technological advances that are facilitating culture-dependent and culture-independent access to new chemistry from environmental microbiomes with the goal of re-invigorating the small molecule therapeutics discovery pipeline. We highlight the successful strategies that have emerged and some of the challenges that must be overcome to enable the development of high-throughput methods for natural product discovery from complex microbial communities.

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“…Thailandamide lactone (4) presented moderate antiproliferative activity against human tumor cell lines. 12,13 The thailandepsins also isolated from B. thailandensis E264 are related to FK228 BGC in Chromobacterium violaceum.…”

Section: Burkholderia Thailandensis (B Thailandensis)mentioning

confidence: 99%

An Insight Into the Intraspecific Variation of Biosynthetic Gene Clusters Between Strains ofBurkholderia thailandensisspp.

Baldim¹,

Soares²

2016

Journal of the Brazilian Chemical Society

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The present study aimed to investigate the intraspecific variation of biosynthetic gene clusters (BGCs) in different strains of Burkholderia thailandensis in order to guide natural products (NPs) discovery process. Species from the genus Burkholderia are emerging as promising species due to their biosynthetic potential. Through genome-mining strategies, it was able to identify that B. thailandensis strains present major genome variation between chromosomes I and II and the standard. The positioning of BGCs also differs when comparing each chromosome. Classical pathways as well as terpene and bacteriocins were commonly identified to all of them and BGCs related to the production of nonribosomal peptides and polyketides compounds are often noticed. In addition, hybrids BGCs were identified as using large amount of replicon information. Among all species studied, the strain MSMB121 showed greater potential for biosynthesizing novel natural products and after phylogenetic analysis, the likelihood of recognizing sites of novelties was assigned. Keywords: Burkholderia thailandensis, genome-mining, natural products discovery IntroductionSpecies of the genus Burkholderia have emerged as owing promising biosynthetic capability for diverse natural products (NPs). Recently, a remarkable study about the potential of microorganisms in biosynthesizing NPs pointed that proteobacteria species present large number of biosynthetic gene clusters (BGCs).1 This global analysis included species from the genus Pseudomonas spp. and Burkholderia spp. as containing the majority of BGCs counting for proteobacteria representatives. However, the great interest is related to Burkholderia spp., once Pseudomonas spp. are extensively studied. About the likelihood of producing novel NPs, Burkholderia genomes present, statistically, higher percentage of thiotemplate modular systems than those of bacilli, cyanobacteria, myxobacteria and fungi, and is only second to that of actinobacteria.2 These modular systems are related to the production of many classes of pharmaceutical compounds, including polyketide synthase (PKS)-and nonribosomal peptide synthase (NRPS)-related products. 3According to the German Collection of Microorganisms and Cell Cultures (DSMZ) database, the genus Burkholderia comprises more than 90 species. These species inhabit the most diverse types of ecological niches such as soil, water, rhizosphere and plant surface. 4NPs from Burkholderia spp. are structurally and functionally diverse, comprising benzoquinone; lactone; and polyene compounds, lasso peptides, nonribosomal peptides, statins, and polyketides. These compounds present important biological activities. In addition, some of these small molecules from Burkholderia sp. have entered as drug candidates to preclinical evaluation. 5Burkholderia thailandensis (B. thailandensis) E264 presented a high level of similarity to the BGC BTH-II0204-207 from Burkholderia pseudomallei (B. pseudomallei) K96243 related to the production of betulinan/terferol analogues.6 Experiments indicat...

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Induced Biosynthesis of Cryptic Polyketide Metabolites in a Burkholderia thailandensis Quorum Sensing Mutant

Cited by 76 publications

References 26 publications

Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis

Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis

Mining the Metabiome: Identifying Novel Natural Products from Microbial Communities

An Insight Into the Intraspecific Variation of Biosynthetic Gene Clusters Between Strains ofBurkholderia thailandensisspp.

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