The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery.
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ABSTRACT:
SUBMITTER: Jensen PR
PROVIDER: S-EPMC4414829 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
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The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery.
Jensen Paul R PR Moore Bradley S BS Fenical William W
Natural product reports 20150501 5
This review covers the initial discovery of the marine actinomycete genus Salinispora through its development as a model for natural product research. A focus is placed on the novel chemical structures reported with reference to their biological activities and the synthetic and biosynthetic studies they have inspired. The time line of discoveries progresses from more traditional bioassay-guided approaches through the application of genome mining and genetic engineering techniques that target the ...[more]
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Project description:The molecular fingerprinting technique terminal-restriction fragment length polymorphism (T-RFLP) was used in combination with sequence-based approaches to evaluate the geographic distribution of secondary metabolite biosynthetic genes in strains of the marine actinomycete Salinispora arenicola. This study targeted ketosynthase (KS) domains from type I polyketide synthase (PKS) genes and revealed four distinct clusters, the largest of which was comprised of strains from all six global locations sampled. The remaining strains fell into three smaller clusters comprised of strains derived entirely from the Red Sea, the Sea of Cortez, or around the Island of Guam. These results reveal variation in the secondary metabolite gene collectives maintained by strains that are largely clonal at the 16S rRNA level. The location specificities of the three smaller clusters provide evidence that collections of secondary metabolite genes in subpopulations of S. arenicola are endemic to these locations. Cloned KS sequences support the maintenance of distinct sets of biosynthetic genes in the strains associated with each cluster and include four that had not previously been detected in S. arenicola. Two of these new sequences were observed only in strains derived from Guam or the Sea of Cortez. Transcriptional analysis of one of the new KS sequences in conjunction with the production of the polyketide arenicolide A supports a link between this sequence and the associated biosynthetic pathway. From the perspective of natural product discovery, these results suggest that screening populations from distant locations can enhance the discovery of new natural products and provides further support for the use of molecular fingerprinting techniques, such as T-RFLP, to rapidly identify strains that possess distinct sets of biosynthetic genes.
| S-EPMC3165397 | biostudies-literature
Project description:Access to genome sequence data has challenged traditional natural product discovery paradigms by revealing that the products of most bacterial biosynthetic pathways have yet to be discovered. Despite the insight afforded by this technology, little is known about the diversity and distributions of natural product biosynthetic pathways among bacteria and how they evolve to generate structural diversity. Here we analyze genome sequence data derived from 75 strains of the marine actinomycete genus Salinispora for pathways associated with polyketide and nonribosomal peptide biosynthesis, the products of which account for some of today's most important medicines. The results reveal high levels of diversity, with a total of 124 pathways identified and 229 predicted with continued sequencing. Recent horizontal gene transfer accounts for the majority of pathways, which occur in only one or two strains. Acquired pathways are incorporated into genomic islands and are commonly exchanged within and between species. Acquisition and transfer events largely involve complete pathways, which subsequently evolve by gene gain, loss, and duplication followed by divergence. The exchange of similar pathway types at the precise chromosomal locations in different strains suggests that the mechanisms of integration include pathway-level homologous recombination. Despite extensive horizontal gene transfer there is clear evidence of species-level vertical inheritance, supporting the concept that secondary metabolites represent functional traits that help define Salinispora species. The plasticity of the Salinispora secondary metabolome provides an effective mechanism to maximize population-level secondary metabolite diversity while limiting the number of pathways maintained within any individual genome.
| S-EPMC3970525 | biostudies-literature
Project description:Here we report associations between secondary metabolite production and phylogenetically distinct but closely related marine actinomycete species belonging to the genus Salinispora. The pattern emerged in a study that included global collection sites, and it indicates that secondary metabolite production can be a species-specific, phenotypic trait associated with broadly distributed bacterial populations. Associations between actinomycete phylotype and chemotype revealed an effective, diversity-based approach to natural product discovery that contradicts the conventional wisdom that secondary metabolite production is strain specific. The structural diversity of the metabolites observed, coupled with gene probing and phylogenetic analyses, implicates lateral gene transfer as a source of the biosynthetic genes responsible for compound production. These results conform to a model of selection-driven pathway fixation occurring subsequent to gene acquisition and provide a rare example in which demonstrable physiological traits have been correlated to the fine-scale phylogenetic architecture of an environmental bacterial community.
| S-EPMC1828645 | biostudies-literature
Project description:Recent fermentation studies have identified actinomycetes of the marine-dwelling genus Salinispora as prolific natural product producers. To further evaluate their biosynthetic potential, we sequenced the 5,183,331-bp S. tropica CNB-440 circular genome and analyzed all identifiable secondary natural product gene clusters. Our analysis shows that S. tropica dedicates a large percentage of its genome ( approximately 9.9%) to natural product assembly, which is greater than previous Streptomyces genome sequences as well as other natural product-producing actinomycetes. The S. tropica genome features polyketide synthase systems of every known formally classified family, nonribosomal peptide synthetases, and several hybrid clusters. Although a few clusters appear to encode molecules previously identified in Streptomyces species, the majority of the 17 biosynthetic loci are novel. Specific chemical information about putative and observed natural product molecules is presented and discussed. In addition, our bioinformatic analysis not only was critical for the structure elucidation of the polyene macrolactam salinilactam A, but its structural analysis aided the genome assembly of the highly repetitive slm loci. This study firmly establishes the genus Salinispora as a rich source of drug-like molecules and importantly reveals the powerful interplay between genomic analysis and traditional natural product isolation studies.
| S-EPMC1965521 | biostudies-literature
Project description:Salinispora is the first obligate marine genus within the order Actinomycetales and a productive source of biologically active secondary metabolites. Despite a worldwide, tropical or subtropical distribution in marine sediments, only two Salinispora species have thus far been cultivated, suggesting limited species-level diversity. To further explore Salinispora diversity and distributions, the phylogenetic diversity of more than 350 strains isolated from sediments collected around the Bahamas was examined, including strains cultured using new enrichment methods. A culture-independent method, using a Salinispora-specific seminested PCR technique, was used to detect Salinispora from environmental DNA and estimate diversity. Overall, the 16S rRNA gene sequence diversity of cultured strains agreed well with that detected in the environmental clone libraries. Despite extensive effort, no new species level diversity was detected, and 97% of the 105 strains examined by restriction fragment length polymorphism belonged to one phylotype (S. arenicola). New intraspecific diversity was detected in the libraries, including an abundant new phylotype that has yet to be cultured, and a new depth record of 1,100 m was established for the genus. PCR-introduced error, primarily from Taq polymerase, significantly increased clone library sequence diversity and, if not masked from the analyses, would have led to an overestimation of total diversity. An environmental DNA extraction method specific for vegetative cells provided evidence for active actinomycete growth in marine sediments while indicating that a majority of sediment samples contained predominantly Salinispora spores at concentrations that could not be detected in environmental clone libraries. Challenges involved with the direct sequence-based detection of spore-forming microorganisms in environmental samples are discussed.
| S-EPMC1287694 | biostudies-literature
Project description:BackgroundThere is little published regarding metabolism of Salinispora species. In continuation with efforts performed towards this goal, this study is focused on new insights into the metabolism of the three-identified species of Salinispora using constraints-based modeling. At present, only one manually curated genome-scale metabolic model (GSM) for Salinispora tropica strain CNB-440T has been built despite the role of Salinispora strains in drug discovery.ResultsHere, we updated, and expanded the scope of the model of Salinispora tropica CNB-440T, and GSMs were constructed for two sequenced type strains covering the three-identified species. We also constructed a Salinispora core model that contains the genes shared by 93 sequenced strains and a few non-conserved genes associated with essential reactions. The models predicted no auxotrophies for essential amino acids, which was corroborated experimentally using a defined minimal medium (DMM). Experimental observations suggest possible sulfur accumulation. The Core metabolic content shows that the biosynthesis of specialised metabolites is the less conserved subsystem. Sets of reactions were analyzed to explore the differences between the reconstructions. Unique reactions associated to each GSM were mainly due to genome sequence data except for the ST-CNB440 reconstruction. In this case, additional reactions were added from experimental evidence. This reveals that by reaction content the ST-CNB440 model is different from the other species models. The differences identified in reaction content between models gave rise to different functional predictions of essential nutrient usage by each species in DMM. Furthermore, models were used to evaluate in silico single gene knockouts under DMM and complex medium. Cluster analysis of these results shows that ST-CNB440, and SP-CNR114 models are more similar when considering predicted essential genes.ConclusionsModels were built for each of the three currently identified Salinispora species, and a core model representing the conserved metabolic capabilities of Salinispora was constructed. Models will allow in silico metabolism studies of Salinispora strains, and help researchers to guide and increase the production of specialised metabolites. Also, models can be used as templates to build GSMs models of closely related organisms with high biotechnology potential.
| S-EPMC6341766 | biostudies-literature
Project description:Many bacteria produce siderophores for sequestration of growth-essential iron. Analysis of the Salinispora genomes suggests that these marine actinomycetes support multiple hydroxamate- and phenolate-type siderophore pathways. We isolated and characterized desferrioxamines (DFOs) B and E from all three recognized Salinispora species and linked their biosyntheses in S. tropica CNB-440 and S. arenicola CNS-205 to the des locus through PCR-directed mutagenesis. Gene inactivation of the predicted iron-chelator biosynthetic loci sid2-4 did not abolish siderophore chemistry. Additionally, these pathways could not restore the native growth characteristics of the des mutants in iron-limited media, although differential iron-dependent regulation was observed for the yersiniabactin-like sid2 pathway. Consequently, this study indicates that DFOs are the primary siderophores in laboratory cultures of Salinispora.
| S-EPMC4209017 | biostudies-literature
Project description:Comparative genomics is providing new opportunities to address the diversity and distributions of genes encoding the biosynthesis of specialized metabolites. An analysis of 119 genome sequences representing three closely related species of the marine actinomycete genus Salinispora reveals extraordinary biosynthetic diversity in the form of 176 distinct biosynthetic gene clusters (BGCs) of which only 24 have been linked to their products. Remarkably, more than half of the BGCs were observed in only one or two strains, suggesting they were acquired relatively recently in the evolutionary history of the genus. These acquired gene clusters are concentrated in specific genomic islands, which represent hot spots for BGC acquisition. While most BGCs are stable in terms of their chromosomal position, others migrated to different locations or were exchanged with unrelated gene clusters suggesting a plug and play type model of evolution that provides a mechanism to test the relative fitness effects of specialized metabolites. Transcriptome analyses were used to address the relationships between BGC abundance, chromosomal position and product discovery. The results indicate that recently acquired BGCs can be functional and that complex evolutionary processes shape the micro-diversity of specialized metabolism observed in closely related environmental bacteria.
| S-EPMC5599359 | biostudies-literature
Project description:The marine actinomycete genus Salinispora is composed of three closely related species. These bacteria are a rich source of secondary metabolites, which are produced in species-specific patterns. This study examines the distribution and phylogenetic relationships of genes involved in the biosynthesis of secondary metabolites in the salinosporamide and staurosporine classes, which have been reported for S. tropica and S. arenicola, respectively. The focus is on "Salinispora pacifica," the most recently discovered and phylogenetically diverse member of the genus. Of 61 S. pacifica strains examined, 15 tested positive for a ketosynthase (KS) domain linked to the biosynthesis of salinosporamide K, a new compound in the salinosporamide series. Compound production was confirmed in two strains, and the domain phylogeny supports vertical inheritance from a common ancestor shared with S. tropica, which produces related compounds in the salinosporamide series. There was no evidence for interspecies recombination among salA KS sequences, providing further support for the geographic isolation of these two salinosporamide-producing lineages. In addition, staurosporine production is reported for the first time for S. pacifica, with 24 of 61 strains testing positive for staD, a key gene involved in the biosynthesis of this compound. High levels of recombination were observed between staD alleles in S. pacifica and the cooccurring yet more distantly related S. arenicola, which produces a similar series of staurosporines. The distributions and phylogenies of the biosynthetic genes examined provide insight into the complex processes driving the evolution of secondary metabolism among closely related bacterial species.
| S-EPMC3194868 | biostudies-literature
Project description:Three new cyclohexadepsipeptides, arenamides A-C (1-3), were isolated from the fermentation broth of a marine bacterial strain identified as Salinispora arenicola. The planar structures of these compounds were assigned by detailed interpretation of NMR and MS/MS spectroscopic data. The absolute configurations of the amino acids, and those of the chiral centers on the side chain, were established by application of the Marfey and modified Mosher methods. The effect of arenamides A and B on NFkappaB activity was studied with stably transfected 293/NFkappaB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNF). Arenamides A (1) and B (2) blocked TNF-induced activation in a dose- and time-dependent manner with IC(50) values of 3.7 and 1.7 microM, respectively. In addition, the compounds inhibited nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production with lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Moderate cytotoxicity was observed with the human colon carcinoma cell line HCT-116, but no cytotoxic effect was noted with cultured RAW cells. Taken together, these data suggest that the chemoprevention and anti-inflammatory characteristics of arenamides A and B warrant further investigation.
| S-EPMC2837138 | biostudies-other