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A New Dioic Acid from a wbl Gene Mutant of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66.

ABSTRACT: The wblA_so gene functions as a global regulatory gene in a negative manner in deepsea-derived Streptomyces somaliensis SCSIO ZH66. A new dioic acid (1) as well as two known butenolides (2 and 3) were isolated from the ?wblA_so mutant strain of S. somaliensis SCSIO ZH66. The structure of 1 was elucidated by a combination of spectroscopic analyses, including MS and NMR techniques. In the cell growth inhibitory evaluation, compound 3 exhibited moderate activity against the human hepatic carcinoma cell line (Huh7.5) with an IC₅₀ value of 19.4 ?g/mL, while compounds 1 and 2 showed null activity up to 100 ?g/mL.

SUBMITTER: Huang H

PROVIDER: S-EPMC5082332 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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A New Dioic Acid from a wbl Gene Mutant of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66.

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

Marine drugs 20161017 10

The wblAso gene functions as a global regulatory gene in a negative manner in deepsea-derived Streptomyces somaliensis SCSIO ZH66. A new dioic acid (1) as well as two known butenolides (2 and 3) were isolated from the ΔwblAso mutant strain of S. somaliensis SCSIO ZH66. The structure of 1 was elucidated by a combination of spectroscopic analyses, including MS and NMR techniques. In the cell growth inhibitory evaluation, ...[more]

PMID: 27763499

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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

A New Dioic Acid from a wbl Gene Mutant of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66.

Publications

A New Dioic Acid from a wbl Gene Mutant of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66.

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