Dataset Information

Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production.

ABSTRACT: Deepsea microbes are a rich source of novel bioactive compounds, which have developed unique genetic systems as well as biosynthetic pathways compared with those of terrestrial microbes in order to survive in extreme living environment. However, a large variety of deepsea-microbial secondary metabolic pathways remain "cryptic" under the normal laboratory conditions. Manipulation of global regulators is one of the effective approaches for triggering the production of cryptic secondary metabolites. In this study, by combination of various chromatographic purification process, we obtained somalimycin (1), a new antimycin-type depsipeptide, with an unusual substitution of 3-aminosalicylate instead of conserved 3-formamidosalicylate moiety, along with two known (2 and 3) analogs from the ?wblA_so mutant strain of deepsea-derived Streptomyces somaliensis SCSIO ZH66. The structures of 1-3 were elucidated on the basis of extensive spectroscopic analyses including LC-MS and NMR. In the evaluation of potent anti-inflammatory activity, compound 2 exhibited strong inhibitory activity on the IL-5 production in ovalbumin-stimulated splenocytes with IC₅₀ value of 0.57 ?M, while 1 and 3 displayed mild effect (>10 ?M), which might be attributed to their different side-chain substitutions. Moreover, compounds 1-3 showed very weak cytotoxicity against human umbilical vein endothelial cells with LD₅₀ values of 62.6, 34.6, and 192.9 ?M, respectively, which were far over their IL-5 inhibitory activity. These results indicated that these compounds have good potential for further use in anti-inflammatory drug development.

SUBMITTER: Li H

PROVIDER: S-EPMC5395633 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Discovery of Antimycin-Type Depsipeptides from a <i>wbl</i> Gene Mutant Strain of Deepsea-Derived <i>Streptomyces somaliensis</i> SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production.

Li Huayue H Huang Huiming H Hou Lukuan L Ju Jianhua J Li Wenli W

Frontiers in microbiology 20170419

Deepsea microbes are a rich source of novel bioactive compounds, which have developed unique genetic systems as well as biosynthetic pathways compared with those of terrestrial microbes in order to survive in extreme living environment. However, a large variety of deepsea-microbial secondary metabolic pathways remain "cryptic" under the normal laboratory conditions. Manipulation of global regulators is one of the effective approaches for triggering the production of cryptic secondary metabolites ...[more]

PMID: 28469615

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Project description:BackgroundMarine microorganisms are an important source of new drug leads. However, the discovery and sustainable production of these compounds are often hampered due to the unavailable expression of cryptic biosynthetic gene clusters or limited titer. Ribosome engineering and response surface methodology (RSM) integrated strategy was developed in this study to activate cryptic gene cluster in the deepsea-derived Streptomyces somaliensis SCSIO ZH66, and subsequently isolation, structural analysis, and the yield enhancement of the activated compound, anticancer drug lead Fredericamycin A (FDM A), were performed.ResultsIn order to discover novel natural products from marine Streptomyces strains by genome mining strategy, the deepsea-derived S. somaliensis SCSIO ZH66 was subject to ribosome engineering to activate the expression of cryptic gene clusters. A resistant strain ZH66-RIF1 was thereby obtained with 300 μg/mL rifampicin, which accumulated a brown pigment with cytotoxicity on MS plate while absent in the wild type strain. After screening of fermentation conditions, the compound with pigment was purified and identified to be FDM A, indicating that the activation of a cryptic FDM A biosynthetic gene cluster was taken place in strain ZH66-RIF1, and then it was identified to be ascribed to the mutation of R444H in the β subunit of RNA polymerase. To further improve the yield efficiently, nine fermentation medium components were examined for their significance on FDM A production by Plackett-Burman design and Box-Behnken design. The optimum medium composition was achieved by RSM strategy, under which the titer of FDM A reached 679.5 ± 15.8 mg/L after 7 days of fermentation, representing a 3-fold increase compared to the original medium. In terms of short fermentation time and low-cost fermentation medium, strain ZH66-RIF1 would be an ideal alternative source for FDM A production.ConclusionsOur results would hasten the efforts for further development of FDM A as a drug candidate. Moreover, this ribosome engineering and RSM integrated methodology is effective, fast and efficient; it would be applicable to genome mining for novel natural products from other strains.

Dataset Information

Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production.

Publications

Discovery of Antimycin-Type Depsipeptides from a <i>wbl</i> Gene Mutant Strain of Deepsea-Derived <i>Streptomyces somaliensis</i> SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production.

Similar Datasets

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