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Special Issue "New Approaches for Activating Silent Biogenetic Gene Clusters in Marine Microorganisms"

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

Deadline for manuscript submissions: closed (31 May 2015)

Special Issue Editors

Guest Editor
Prof. Dr. Peter Proksch (Website)

Institut für Pharmazeutische Biologie, Universität Düsseldorf, Gebäude 26.23, Universitätsstraße 1, 40225 Düsseldorf, Germany
Phone: 0049-211-8114163
Fax: +49 211 8111923
Interests: marine natural products, marine medicines, chemical ecology
Co-Guest Editor
Dr. Hendrik Niemann

Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, Geb. 26.23, Düsseldorf 40225, Germany
Phone: +49 211 81 14173
Fax: +49 211 81 11923
Interests: life aquatic

Special Issue Information

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs).

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

Published Papers (7 papers)

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Research

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Open AccessArticle Mycemycins A–E, New Dibenzoxazepinones Isolated from Two Different Streptomycetes
Mar. Drugs 2015, 13(10), 6247-6258; doi:10.3390/md13106247
Received: 25 July 2015 / Revised: 17 September 2015 / Accepted: 18 September 2015 / Published: 30 September 2015
PDF Full-text (314 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Five new dibenzoxazepinone derivatives, mycemycins A–E (15), 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 35 from [...] Read more.
Five new dibenzoxazepinone derivatives, mycemycins A–E (15), 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 35 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
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Open AccessArticle High-Level Expression, Purification and Large-Scale Production of l-Methionine γ-Lyase from Idiomarina as a Novel Anti-Leukemic Drug
Mar. Drugs 2015, 13(8), 5492-5507; doi:10.3390/md13085492
Received: 7 May 2015 / Revised: 11 July 2015 / Accepted: 12 August 2015 / Published: 21 August 2015
Cited by 1 | PDF Full-text (1410 KB) | HTML Full-text | XML Full-text
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 [...] 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
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Open AccessArticle Production of Induced Secondary Metabolites by a Co-Culture of Sponge-Associated Actinomycetes, Actinokineospora sp. EG49 and Nocardiopsis sp. RV163
Mar. Drugs 2014, 12(5), 3046-3059; doi:10.3390/md12053046
Received: 7 January 2014 / Revised: 4 March 2014 / Accepted: 10 April 2014 / Published: 22 May 2014
Cited by 14 | PDF Full-text (781 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 110, were isolated from the [...] 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 110, 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
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Open AccessCommunication Phenolic Polyketides from the Co-Cultivation of Marine-Derived Penicillium sp. WC-29-5 and Streptomyces fradiae 007
Mar. Drugs 2014, 12(4), 2079-2088; doi:10.3390/md12042079
Received: 15 January 2014 / Revised: 24 February 2014 / Accepted: 21 March 2014 / Published: 4 April 2014
Cited by 4 | PDF Full-text (762 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Penicillium sp. WC-29-5 was co-cultured with Streptomyces fradiae 007 to produce five natural products (13, 4a and 4b) that were isolated and characterized by spectroscopic analysis. Interestingly, these compounds were found to be different from those produced [...] Read more.
Penicillium sp. WC-29-5 was co-cultured with Streptomyces fradiae 007 to produce five natural products (13, 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

Review

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Open AccessReview The Sound of Silence: Activating Silent Biosynthetic Gene Clusters in Marine Microorganisms
Mar. Drugs 2015, 13(8), 4754-4783; doi:10.3390/md13084754
Received: 5 June 2015 / Revised: 5 June 2015 / Accepted: 27 July 2015 / Published: 31 July 2015
Cited by 10 | PDF Full-text (1002 KB) | HTML Full-text | XML Full-text
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 [...] 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
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Open AccessReview Co-Cultivation—A Powerful Emerging Tool for Enhancing the Chemical Diversity of Microorganisms
Mar. Drugs 2014, 12(2), 1043-1065; doi:10.3390/md12021043
Received: 9 January 2014 / Revised: 23 January 2014 / Accepted: 6 February 2014 / Published: 17 February 2014
Cited by 32 | PDF Full-text (779 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessReview Astaxanthin: Sources, Extraction, Stability, Biological Activities and Its Commercial Applications—A Review
Mar. Drugs 2014, 12(1), 128-152; doi:10.3390/md12010128
Received: 10 October 2013 / Revised: 10 December 2013 / Accepted: 11 December 2013 / Published: 7 January 2014
Cited by 67 | PDF Full-text (952 KB) | HTML Full-text | XML Full-text
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
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