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Marine Drugs
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New Approaches for Activating Silent Biogenetic Gene Clusters in Marine...
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New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (31 May 2015) | Viewed by 150891

Special Issue Editors

Prof. Dr. Peter Proksch

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Guest Editor
Institut für Pharmazeutische Biologie, Universität Düsseldorf, Gebäude 26.23, Universitätsstraße 1, 40225 Düsseldorf, Germany
Interests: marine natural products, marine medicines, chemical ecology
Special Issues, Collections and Topics in MDPI journals
Dr. Hendrik Niemann

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Co-Guest Editor
Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, Geb. 26.23, Düsseldorf 40225, Germany
Interests: life aquatic

Special Issue Information

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Keywords

  • marine microorganisms
  • marine fungi
  • marine bacteria
  • natural products
  • co-cultivation
  • silent biogenetic gene clusters
  • OSMAC
  • Epigenetic modifiers
  • HDAC
  • DNMT
  • SAHA
  • 5-azacytidine
  • valproic acid

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Published Papers (7 papers)

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Research

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314 KiB  
Article
Mycemycins A–E, New Dibenzoxazepinones Isolated from Two Different Streptomycetes
by Ning Liu, Fangying Song, Fei Shang and Ying Huang
Mar. Drugs 2015, 13(10), 6247-6258; https://doi.org/10.3390/md13106247 - 30 Sep 2015
Cited by 14 | Viewed by 6023
Abstract
Five new dibenzoxazepinone derivatives, mycemycins A–E (1–5), were isolated from the ethanol extracts of mycelia of two different streptomycetes. 1 and 2 were isolated from an acidic red soil-derived strain, Streptomyces sp. FXJ1.235, and 3–5 from a [...] Read more.
Five new dibenzoxazepinone derivatives, mycemycins A–E (1–5), were isolated from the ethanol extracts of mycelia of two different streptomycetes. 1 and 2 were isolated from an acidic red soil-derived strain, Streptomyces sp. FXJ1.235, and 3–5 from a gntR gene-disrupted deep-sea strain named Streptomyces olivaceus FXJ8.012Δ1741. The structures of mycemycins were elucidated by a combination of spectroscopic analyses, including 1D- and 2D-NMR techniques. Full article
(This article belongs to the Special Issue New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms)
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1410 KiB  
Article
High-Level Expression, Purification and Large-Scale Production of l-Methionine γ-Lyase from Idiomarina as a Novel Anti-Leukemic Drug
by Kui-Ying Huang, Hai-Yan Hu, Yan-Lai Tang, Feng-Geng Xia, Xue-Qun Luo and Jian-Zhong Liu
Mar. Drugs 2015, 13(8), 5492-5507; https://doi.org/10.3390/md13085492 - 21 Aug 2015
Cited by 13 | Viewed by 6623
Abstract
l-Methionine γ-lyase (MGL), a pyridoxal 5′-phosphate-dependent enzyme, possesses anti-tumor activity. However, the low activity of MGL blocks the anti-tumor effect. This study describes an efficient production process for the recombinant MGL (rMGL) from Idiomarina constructed using the overexpression plasmid in Escherichia coli BL21 [...] Read more.
l-Methionine γ-lyase (MGL), a pyridoxal 5′-phosphate-dependent enzyme, possesses anti-tumor activity. However, the low activity of MGL blocks the anti-tumor effect. This study describes an efficient production process for the recombinant MGL (rMGL) from Idiomarina constructed using the overexpression plasmid in Escherichia coli BL21 (DE3), purification, and large-scale production. The enzyme produced by the transformants accounted for 53% of the total proteins and accumulated at 1.95 mg/mL using a 500 L fermentor. The enzyme was purified to approximately 99% purity using a high-pressure mechanical homogenizer and nickel (Ni) Sepharose 6 Fast Flow (FF) chromatography. Then, the enzyme was polished by gel filtration, the endotoxins were removed using diethyl-aminoethanol (DEAE) Sepharose FF, and the final product was lyophilized with a vacuum freeze dryer at −35 °C. The specific activity of rMGL in the lyophilized powder was up to 108 U/mg. Compared to the control, the enzyme significantly inhibited cellular proliferation in a concentration-dependent manner as tested using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and induced cellular apoptosis as analyzed by Annexin V-fluorescein isothiocyanate (FITC) with fluorescence-activated cell sorting (FACS) in leukemia cells. This paper demonstrated the cloning, overexpression, and large-scale production protocols for rMGL, which enabled rMGL to be used as a novel anti-leukemic drug. Full article
(This article belongs to the Special Issue New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms)
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781 KiB  
Article
Production of Induced Secondary Metabolites by a Co-Culture of Sponge-Associated Actinomycetes, Actinokineospora sp. EG49 and Nocardiopsis sp. RV163
by Yousef Dashti, Tanja Grkovic, Usama Ramadan Abdelmohsen, Ute Hentschel and Ronald J. Quinn
Mar. Drugs 2014, 12(5), 3046-3059; https://doi.org/10.3390/md12053046 - 22 May 2014
Cited by 111 | Viewed by 14345
Abstract
Two sponge-derived actinomycetes, Actinokineospora sp. EG49 and Nocardiopsis sp. RV163, were grown in co-culture and the presence of induced metabolites monitored by 1H NMR. Ten known compounds, including angucycline, diketopiperazine and β-carboline derivatives 1–10, were isolated from the EtOAc [...] Read more.
Two sponge-derived actinomycetes, Actinokineospora sp. EG49 and Nocardiopsis sp. RV163, were grown in co-culture and the presence of induced metabolites monitored by 1H NMR. Ten known compounds, including angucycline, diketopiperazine and β-carboline derivatives 1–10, were isolated from the EtOAc extracts of Actinokineospora sp. EG49 and Nocardiopsis sp. RV163. Co-cultivation of Actinokineospora sp. EG49 and Nocardiopsis sp. RV163 induced the biosynthesis of three natural products that were not detected in the single culture of either microorganism, namely N-(2-hydroxyphenyl)-acetamide (11), 1,6-dihydroxyphenazine (12) and 5a,6,11a,12-tetrahydro-5a,11a-dimethyl[1,4]benzoxazino[3,2-b][1,4]benzoxazine (13a). When tested for biological activity against a range of bacteria and parasites, only the phenazine 12 was active against Bacillus sp. P25, Trypanosoma brucei and interestingly, against Actinokineospora sp. EG49. These findings highlight the co-cultivation approach as an effective strategy to access the bioactive secondary metabolites hidden in the genomes of marine actinomycetes. Full article
(This article belongs to the Special Issue New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms)
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762 KiB  
Communication
Phenolic Polyketides from the Co-Cultivation of Marine-Derived Penicillium sp. WC-29-5 and Streptomyces fradiae 007
by Yi Wang, Liping Wang, Yibin Zhuang, Fandong Kong, Cuixian Zhang and Weiming Zhu
Mar. Drugs 2014, 12(4), 2079-2088; https://doi.org/10.3390/md12042079 - 4 Apr 2014
Cited by 45 | Viewed by 7831
Abstract
Penicillium sp. WC-29-5 was co-cultured with Streptomyces fradiae 007 to produce five natural products (1–3, 4a and 4b) that were isolated and characterized by spectroscopic analysis. Interestingly, these compounds were found to be different from those produced in [...] Read more.
Penicillium sp. WC-29-5 was co-cultured with Streptomyces fradiae 007 to produce five natural products (1–3, 4a and 4b) that were isolated and characterized by spectroscopic analysis. Interestingly, these compounds were found to be different from those produced in discrete fungal and bacterial controls. Among these compounds, the absolute configurations of compounds 4a and 4b were determined for the first time by X-ray single crystal diffraction experiments and electronic circular dichroism (ECD) calculations. An evaluation of the cytotoxic activities of these compounds revealed that 4b was moderately cytotoxic towards HL-60 and H1975 tumor cells with IC50 values of 3.73 and 5.73 µM, respectively, whereas compound 4a was only moderately cytotoxic towards H1975 cells with an IC50 value of 3.97 µM. Full article
(This article belongs to the Special Issue New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms)
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Review

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1002 KiB  
Review
The Sound of Silence: Activating Silent Biosynthetic Gene Clusters in Marine Microorganisms
by F. Jerry Reen, Stefano Romano, Alan D. W. Dobson and Fergal O'Gara
Mar. Drugs 2015, 13(8), 4754-4783; https://doi.org/10.3390/md13084754 - 31 Jul 2015
Cited by 132 | Viewed by 14694
Abstract
Unlocking the rich harvest of marine microbial ecosystems has the potential to both safeguard the existence of our species for the future, while also presenting significant lifestyle benefits for commercial gain. However, while significant advances have been made in the field of marine [...] Read more.
Unlocking the rich harvest of marine microbial ecosystems has the potential to both safeguard the existence of our species for the future, while also presenting significant lifestyle benefits for commercial gain. However, while significant advances have been made in the field of marine biodiscovery, leading to the introduction of new classes of therapeutics for clinical medicine, cosmetics and industrial products, much of what this natural ecosystem has to offer is locked in, and essentially hidden from our screening methods. Releasing this silent potential represents a significant technological challenge, the key to which is a comprehensive understanding of what controls these systems. Heterologous expression systems have been successful in awakening a number of these cryptic marine biosynthetic gene clusters (BGCs). However, this approach is limited by the typically large size of the encoding sequences. More recently, focus has shifted to the regulatory proteins associated with each BGC, many of which are signal responsive raising the possibility of exogenous activation. Abundant among these are the LysR-type family of transcriptional regulators, which are known to control production of microbial aromatic systems. Although the environmental signals that activate these regulatory systems remain unknown, it offers the exciting possibility of evoking mimic molecules and synthetic expression systems to drive production of potentially novel natural products in microorganisms. Success in this field has the potential to provide a quantum leap forward in medical and industrial bio-product development. To achieve these new endpoints, it is clear that the integrated efforts of bioinformaticians and natural product chemists will be required as we strive to uncover new and potentially unique structures from silent or cryptic marine gene clusters. Full article
(This article belongs to the Special Issue New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms)
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779 KiB  
Review
Co-Cultivation—A Powerful Emerging Tool for Enhancing the Chemical Diversity of Microorganisms
by Andreas Marmann, Amal H. Aly, Wenhan Lin, Bingui Wang and Peter Proksch
Mar. Drugs 2014, 12(2), 1043-1065; https://doi.org/10.3390/md12021043 - 17 Feb 2014
Cited by 283 | Viewed by 21532
Abstract
Marine-derived bacteria and fungi are promising sources of novel bioactive compounds that are important for drug discovery programs. However, as encountered in terrestrial microorganisms there is a high rate of redundancy that results in the frequent re-discovery of known compounds. Apparently only a [...] Read more.
Marine-derived bacteria and fungi are promising sources of novel bioactive compounds that are important for drug discovery programs. However, as encountered in terrestrial microorganisms there is a high rate of redundancy that results in the frequent re-discovery of known compounds. Apparently only a part of the biosynthetic genes that are harbored by fungi and bacteria are transcribed under routine laboratory conditions which involve cultivation of axenic microbial strains. Many biosynthetic genes remain silent and are not expressed in vitro thereby seriously limiting the chemical diversity of microbial compounds that can be obtained through fermentation. In contrast to this, co-cultivation (also called mixed fermentation) of two or more different microorganisms tries to mimic the ecological situation where microorganisms always co-exist within complex microbial communities. The competition or antagonism experienced during co-cultivation is shown to lead to a significantly enhanced production of constitutively present compounds and/or to an accumulation of cryptic compounds that are not detected in axenic cultures of the producing strain. This review highlights the power of co-cultivation for increasing the chemical diversity of bacteria and fungi drawing on published studies from the marine and from the terrestrial habitat alike. Full article
(This article belongs to the Special Issue New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms)
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952 KiB  
Review
Astaxanthin: Sources, Extraction, Stability, Biological Activities and Its Commercial Applications—A Review
by Ranga Rao Ambati, Siew-Moi Phang, Sarada Ravi and Ravishankar Gokare Aswathanarayana
Mar. Drugs 2014, 12(1), 128-152; https://doi.org/10.3390/md12010128 - 7 Jan 2014
Cited by 1513 | Viewed by 78796
Abstract
There is currently much interest in biological active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Astaxanthin (3,3′-dihydroxy-β, β′-carotene-4,4′-dione) is a xanthophyll carotenoid, contained in Haematococcus pluvialis, Chlorella zofingiensis, [...] Read more.
There is currently much interest in biological active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Astaxanthin (3,3′-dihydroxy-β, β′-carotene-4,4′-dione) is a xanthophyll carotenoid, contained in Haematococcus pluvialis, Chlorella zofingiensis, Chlorococcum, and Phaffia rhodozyma. It accumulates up to 3.8% on the dry weight basis in H. pluvialis. Our recent published data on astaxanthin extraction, analysis, stability studies, and its biological activities results were added to this review paper. Based on our results and current literature, astaxanthin showed potential biological activity in in vitro and in vivo models. These studies emphasize the influence of astaxanthin and its beneficial effects on the metabolism in animals and humans. Bioavailability of astaxanthin in animals was enhanced after feeding Haematococcus biomass as a source of astaxanthin. Astaxanthin, used as a nutritional supplement, antioxidant and anticancer agent, prevents diabetes, cardiovascular diseases, and neurodegenerative disorders, and also stimulates immunization. Astaxanthin products are used for commercial applications in the dosage forms as tablets, capsules, syrups, oils, soft gels, creams, biomass and granulated powders. Astaxanthin patent applications are available in food, feed and nutraceutical applications. The current review provides up-to-date information on astaxanthin sources, extraction, analysis, stability, biological activities, health benefits and special attention paid to its commercial applications. Full article
(This article belongs to the Special Issue New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms)
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