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

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 62229

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Special Issue Editors

Prof. Dr. Kui Hong

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Guest Editor

Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Interests: microbial systematic guided marine microbial drug resources (culture, compounds and genes): ecology, collection, isolation and identification; genomics guided marine microbial natural products discovery and biosynthesis

Prof. Dr. Changsheng Zhang

E-Mail Website
Guest Editor

Key Laboratory of Tropical Marine Bio-Resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China
Interests: marine actinobacteria; marine natural products; antimicrobial activity; antitumor activity; marine drug development; biosynthesis of marine polycyclic compounds; genome mining of marine actinomycetes

Prof. Dr. Alan Dobson

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Guest Editor

School of Microbiology, University College Cork, Cork, Ireland
Interests: marine biotechnology; marine natural products; antibiotics drug discovery; marine enzymes; marine microbial ecology; metagenomics; genomics.

Special Issue Information

Dear Colleagues,

Most of the bioactive secondary metabolites for drug discovery isolated from marine microorganisms have been discovered to date using classical bioassay-guided regimes. This process is currently undergoing significant changes primarily as a result of rapid developments in sequencing technology, synthetic biology and bioinformatics. As increasing numbers of whole-genome sequences become available for marine microorganisms, genome mining has become a very attractive tool for drug discovery. Bioinformatic-based approaches are typically employed to screen, and subsequently identify, novel gene clusters, many of which are responsible for the production of the novel molecules. Many genomes appear however to possess “silent” or cryptic biosynthetic gene clusters, the products of which appear to be regulated by a variety of environmental factors, and therefore remain largely undetected.

In this Special Issue, we focus on the rich genomic resources present within the genomes of marine microorganisms and the use of recently developed tools and technologies to exploit this genetic richness, to facilitate the discovery or find new bioactive molecules with potential biopharmaceutical applications.

For this Special Issue of Marine Drugs, we urge you to consider publishing your review paper or original research in the areas listed below:

Bioinformatic tools and their application in genome mining for secondary metabolites
Genome mining approaches for the identification of novel secondary metabolites
Merging ecology (physical, chemical factors or co-culture) with microbial genome mining for secondary metabolites’ discovery
Heterologous systems for the expression of gene clusters to identify novel metabolites
Unlocking cryptic pathways, employing genomic based approaches
Cutting-edge technology in genome editing and novel metabolites identification

Prof. Dr. Kui Hong
Prof. Dr. Changsheng Zhang
Prof. Dr. Alan Dobson
Guest Editors

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind 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 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Genome mining
Secondary metabolites
Natural products
Cryptic gene clusters
Genome editing
Heterologous expression
Cryptic gene activation

Related Special Issue

Natural Product Genomics and Metabolomics of Marine Bacteria in Marine Drugs (12 articles)

Published Papers (11 papers)

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Research

Jump to: Review, Other

14 pages, 1879 KiB

Open AccessArticle

Genome Mining of Marine-Derived Streptomyces sp. SCSIO 40010 Leads to Cytotoxic New Polycyclic Tetramate Macrolactams

by Wei Liu, Wenjun Zhang, Hongbo Jin, Qingbo Zhang, Yuchan Chen, Xiaodong Jiang, Guangtao Zhang, Liping Zhang, Weimin Zhang, Zhigang She and Changsheng Zhang

Mar. Drugs 2019, 17(12), 663; https://doi.org/10.3390/md17120663 - 25 Nov 2019

Cited by 22 | Viewed by 3671

Abstract

Polycyclic tetramate macrolactams (PTMs) biosynthetic gene cluster are widely distributed in different bacterial types, especially in Streptomyces species. The mining of the genomic data of marine-derived Streptomyces sp. SCSIO 40010 reveals the presence of a putative PTM-encoding biosynthetic gene cluster (ptm′ BGC) that features a genetic organization for potentially producing 5/5/6 type of carbocyclic ring-containing PTMs. A fermentation of Streptomyces sp. SCSIO 40010 led to the isolation and characterization of six new PTMs 1–6. Comprehensive spectroscopic analysis assigned their planar structures and relative configurations, and their absolute configurations were deduced by comparing the experimental electronic circular dichroism (ECD) spectra with the reported spectra of the known PTMs. Intriguingly, compounds 1–6 were determined to have a trans-orientation of H-10/H-11 at the first 5-membered ring, being distinct from the cis-orientation in their known PTM congeners. PTMs 1–5 displayed cytotoxicity against several cancer cell lines, with IC₅₀ values that ranged from 2.47 to 17.68 µM. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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18 pages, 3576 KiB

Open AccessArticle

Comparative Genomic Insights into Secondary Metabolism Biosynthetic Gene Cluster Distributions of Marine Streptomyces

by Lin Xu, Kai-Xiong Ye, Wen-Hua Dai, Cong Sun, Lian-Hua Xu and Bing-Nan Han

Mar. Drugs 2019, 17(9), 498; https://doi.org/10.3390/md17090498 - 26 Aug 2019

Cited by 29 | Viewed by 5347

Abstract

Bacterial secondary metabolites have huge application potential in multiple industries. Biosynthesis of bacterial secondary metabolites are commonly encoded in a set of genes that are organized in the secondary metabolism biosynthetic gene clusters (SMBGCs). The development of genome sequencing technology facilitates mining bacterial SMBGCs. Marine Streptomyces is a valuable resource of bacterial secondary metabolites. In this study, 87 marine Streptomyces genomes were obtained and carried out into comparative genomic analysis, which revealed their high genetic diversity due to pan-genomes owning 123,302 orthologous clusters. Phylogenomic analysis indicated that the majority of Marine Streptomyces were classified into three clades named Clade I, II, and III, containing 23, 38, and 22 strains, respectively. Genomic annotations revealed that SMBGCs in the genomes of marine Streptomyces ranged from 16 to 84. Statistical analysis pointed out that phylotypes and ecotypes were both associated with SMBGCs distribution patterns. The Clade I and marine sediment-derived Streptomyces harbored more specific SMBGCs, which consisted of several common ones; whereas the Clade II and marine invertebrate-derived Streptomyces have more SMBGCs, acting as more plentiful resources for mining secondary metabolites. This study is beneficial for broadening our knowledge about SMBGC distribution patterns in marine Streptomyces and developing their secondary metabolites in the future. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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15 pages, 2631 KiB

Open AccessArticle

Biosynthetic Potential of a Novel Antarctic Actinobacterium Marisediminicola antarctica ZS314^T Revealed by Genomic Data Mining and Pigment Characterization

by Li Liao, Shiyuan Su, Bin Zhao, Chengqi Fan, Jin Zhang, Huirong Li and Bo Chen

Mar. Drugs 2019, 17(7), 388; https://doi.org/10.3390/md17070388 - 01 Jul 2019

Cited by 17 | Viewed by 3698

Abstract

Rare actinobacterial species are considered as potential resources of new natural products. Marisediminicola antarctica ZS314^T is the only type strain of the novel actinobacterial genus Marisediminicola isolated from intertidal sediments in East Antarctica. The strain ZS314^T was able to produce reddish orange pigments at low temperatures, showing characteristics of carotenoids. To understand the biosynthetic potential of this strain, the genome was completely sequenced for data mining. The complete genome had 3,352,609 base pairs (bp), much smaller than most genomes of actinomycetes. Five biosynthetic gene clusters (BGCs) were predicted in the genome, including a gene cluster responsible for the biosynthesis of C50 carotenoid, and four additional BGCs of unknown oligosaccharide, salinixanthin, alkylresorcinol derivatives, and NRPS (non-ribosomal peptide synthetase) or amino acid-derived compounds. Further experimental characterization indicated that the strain may produce C.p.450-like carotenoids, supporting the genomic data analysis. A new xanthorhodopsin gene was discovered along with the analysis of the salinixanthin biosynthetic gene cluster. Since little is known about this genus, this work improves our understanding of its biosynthetic potential and provides opportunities for further investigation of natural products and strategies for adaptation to the extreme Antarctic environment. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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11 pages, 2533 KiB

Open AccessArticle

Chrysoxanthones A–C, Three New Xanthone–Chromanone Heterdimers from Sponge-Associated Penicillium chrysogenum HLS111 Treated with Histone Deacetylase Inhibitor

by Xin Zhen, Ting Gong, Yan-Hua Wen, Dao-Jiang Yan, Jing-Jing Chen and Ping Zhu

Mar. Drugs 2018, 16(10), 357; https://doi.org/10.3390/md16100357 - 01 Oct 2018

Cited by 20 | Viewed by 3637

Abstract

By treating with histone-deacetylase inhibitor valproate sodium, three new heterdimeric tetrahydroxanthone–chromanone lactones chrysoxanthones A–C (1–3), along with 17 known compounds were isolated from a sponge-associated Penicillium chrysogenum HLS111. The planar structures of chrysoxanthones A–C were elucidated by means of spectroscopic analyses, including MS, 1D, and 2D NMR. Their absolute configurations were established by electronic circular dichroism (ECD) calculations. Chrysoxanthones A–C exhibited moderate antibacterial activities against Bacillus subtilis with minimum inhibitory concentration (MIC) values of 5–10 μg/mL. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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17 pages, 1872 KiB

Open AccessArticle

Characterization of the Microbial Population Inhabiting a Solar Saltern Pond of the Odiel Marshlands (SW Spain)

by Patricia Gómez-Villegas, Javier Vigara and Rosa León

Mar. Drugs 2018, 16(9), 332; https://doi.org/10.3390/md16090332 - 12 Sep 2018

Cited by 17 | Viewed by 4023

Abstract

The solar salterns located in the Odiel marshlands, in southwest Spain, are an excellent example of a hypersaline environment inhabited by microbial populations specialized in thriving under conditions of high salinity, which remains poorly explored. Traditional culture-dependent taxonomic studies have usually under-estimated the biodiversity in saline environments due to the difficulties that many of these species have to grow at laboratory conditions. Here we compare two molecular methods to profile the microbial population present in the Odiel saltern hypersaline water ponds (33% salinity). On the one hand, the construction and characterization of two clone PCR amplified-16S rRNA libraries, and on the other, a high throughput 16S rRNA sequencing approach based on the Illumina MiSeq platform. The results reveal that both methods are comparable for the estimation of major genera, although massive sequencing provides more information about the less abundant ones. The obtained data indicate that Salinibacter ruber is the most abundant genus, followed by the archaea genera, Halorubrum and Haloquadratum. However, more than 100 additional species can be detected by Next Generation Sequencing (NGS). In addition, a preliminary study to test the biotechnological applications of this microbial population, based on its ability to produce and excrete haloenzymes, is shown. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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16 pages, 1097 KiB

Open AccessArticle

Stress-Driven Discovery of New Angucycline-Type Antibiotics from a Marine Streptomyces pratensis NA-ZhouS1

by Najeeb Akhter, Yaqin Liu, Bibi Nazia Auckloo, Yutong Shi, Kuiwu Wang, Juanjuan Chen, Xiaodan Wu and Bin Wu

Mar. Drugs 2018, 16(9), 331; https://doi.org/10.3390/md16090331 - 12 Sep 2018

Cited by 32 | Viewed by 5382

Abstract

Natural products from marine actinomycetes remain an important resource for drug discovery, many of which are produced by the genus, Streptomyces. However, in standard laboratory conditions, specific gene clusters in microbes have long been considered silent or covert. Thus, various stress techniques activated latent gene clusters leading to isolation of potential metabolites. This study focused on the analysis of two new angucycline antibiotics isolated from the culture filtrate of a marine Streptomyces pratensis strain NA-ZhouS1, named, stremycin A (1) and B (2) which were further determined based on spectroscopic techniques such as high resolution time of flight mass spectrometry (HR-TOF-MS), 1D, and 2D nuclear magnetic resonance (NMR) experiments. In addition, four other known compounds, namely, 2-[2-(3,5-dimethyl-2-oxo-cyclohexyl)-6-oxo-tetrahydro-pyran-4yl]-acetamide (3), cyclo[l-(4-hydroxyprolinyl)-l-leucine] (4), 2-methyl-3H-quinazoline-4-one (5), and menthane derivative, 3-(hydroxymethyl)-6-isopropyl-10,12-dioxatricyclo[7.2.1.0]dodec-4-en-8-one (6) were obtained and elucidated by means of 1D NMR spectrometry. Herein, we describe the “Metal Stress Technique” applied in the discovery of angucyclines, a distinctive class of antibiotics that are commonly encoded in microbiomes but have never been reported in “Metal Stress” based discovery efforts. Novel antibiotics 1 and 2 exhibited antimicrobial activities against Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus (MRSA), Klebsiella pneumonia, and Escherichia coli with equal minimum inhibitory concentration (MIC) values of 16 µg/mL, while these antibiotics showed inhibition against Bacillus subtilis at MIC value of approximately 8–16 µg/mL, respectively. As a result, the outcome of this investigation revealed that metal stress is an effective technique in unlocking the biosynthetic potential and resulting production of novel antibiotics. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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14 pages, 1280 KiB

Open AccessArticle

Bacillibactin and Bacillomycin Analogues with Cytotoxicities against Human Cancer Cell Lines from Marine Bacillus sp. PKU-MA00093 and PKU-MA00092

by Mengjie Zhou, Fawang Liu, Xiaoyan Yang, Jing Jin, Xin Dong, Ke-Wu Zeng, Dong Liu, Yingtao Zhang, Ming Ma and Donghui Yang

Mar. Drugs 2018, 16(1), 22; https://doi.org/10.3390/md16010022 - 10 Jan 2018

Cited by 31 | Viewed by 7044

Abstract

Nonribosomal peptides from marine Bacillus strains have received considerable attention for their complex structures and potent bioactivities. In this study, we carried out PCR-based genome mining for potential nonribosomal peptides producers from our marine bacterial library. Twenty-one “positive” strains were screened out from 180 marine bacterial strains, and subsequent small-scale fermentation, HPLC and phylogenetic analysis afforded Bacillus sp. PKU-MA00092 and PKU-MA00093 as two candidates for large-scale fermentation and isolation. Ten nonribosomal peptides, including four bacillibactin analogues (1–4) and six bacillomycin D analogues (5–10) were discovered from Bacillus sp. PKU-MA00093 and PKU-MA00092, respectively. Compounds 1 and 2 are two new compounds and the ¹H NMR and ¹³C NMR data of compounds 7 and 9 is first provided. All compounds 1–10 were assayed for their cytotoxicities against human cancer cell lines HepG2 and MCF7, and the bacillomycin D analogues 7–10 showed moderate cytotoxicities with IC₅₀ values from 2.9 ± 0.1 to 8.2 ± 0.2 µM. The discovery of 5–10 with different fatty acid moieties gave us the opportunity to reveal the structure-activity relationships of bacillomycin analogues against these human cancer cell lines. These results enrich the structural diversity and bioactivity properties of nonribosomal peptides from marine Bacillus strains. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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1712 KiB

Open AccessArticle

Producing Novel Fibrinolytic Isoindolinone Derivatives in Marine Fungus Stachybotrys longispora FG216 by the Rational Supply of Amino Compounds According to Its Biosynthesis Pathway

by Ying Yin, Qiang Fu, Wenhui Wu, Menghao Cai, Xiangshan Zhou and Yuanxing Zhang

Mar. Drugs 2017, 15(7), 214; https://doi.org/10.3390/md15070214 - 05 Jul 2017

Cited by 20 | Viewed by 4860

Abstract

Many fungi in the Stachybotrys genus can produce various isoindolinone derivatives. These compounds are formed by a spontaneous reaction between a phthalic aldehyde precursor and an ammonium ion or amino compounds. In this study, we suggested the isoindolinone biosynthetic gene cluster in Stachybotrys by genome mining based on three reported core genes. Remarkably, there is an additional nitrate reductase (NR) gene copy in the proposed cluster. NR is the rate-limiting enzyme of nitrate reduction. Accordingly, this cluster was speculated to play a role in the balance of ammonium ion concentration in Stachybotrys. Ammonium ions can be replaced by different amino compounds to create structural diversity in the biosynthetic process of isoindolinone. We tested a rational supply of amino compounds ((±)-3-amino-2-piperidinone, glycine, and l-threonine) in the culture of an isoindolinone high-producing marine fungus, Stachybotrys longispora FG216. As a result, we obtained four new kinds of isoindolinone derivatives (FGFC4–GFC7) by this method. Furthermore, high yields of FGFC4–FGFC7 confirmed the outstanding production capacity of FG216. Among the four new isoindolinone derivatives, FGFC6 and FGFC7 showed promising fibrinolytic activities. The knowledge of biosynthesis pathways may be an important attribute for the discovery of novel bioactive marine natural products. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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Review

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5007 KiB

Open AccessReview

Biogenetic Relationships of Bioactive Sponge Merotriterpenoids

by Thomas E. Smith

Mar. Drugs 2017, 15(9), 285; https://doi.org/10.3390/md15090285 - 10 Sep 2017

Cited by 8 | Viewed by 5301

Abstract

Hydroquinone meroterpenoids, especially those derived from marine sponges, display a wide range of biological activities. However, use of these compounds is limited by their inaccessibility; there is no sustainable supply of these compounds. Furthermore, our knowledge of their metabolic origin remains completely unstudied. In this review, an in depth structural analysis of sponge merotriterpenoids, including the adociasulfate family of kinesin motor protein inhibitors, provides insight into their biosynthesis. Several key structural features provide clues to the relationships between compounds. All adociasulfates appear to be derived from only four different hydroquinone hexaprenyl diphosphate precursors, each varying in the number and position of epoxidations. Proton-initiated cyclization of these precursors can lead to all carbon skeletons observed amongst sponge merotriterpenoids. Consideration of the enzymes involved in the proposed biosynthetic route suggests a bacterial source, and a hypothetical gene cluster was constructed that may facilitate discovery of the authentic pathway from the sponge metagenome. A similar rationale can be extended to other sponge meroterpenoids, for which no biosynthetic pathways have yet been identified. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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3888 KiB

Open AccessReview

Current Status and Future Prospects of Marine Natural Products (MNPs) as Antimicrobials

by Alka Choudhary, Lynn M. Naughton, Itxaso Montánchez, Alan D. W. Dobson and Dilip K. Rai

Mar. Drugs 2017, 15(9), 272; https://doi.org/10.3390/md15090272 - 28 Aug 2017

Cited by 94 | Viewed by 14473

Abstract

The marine environment is a rich source of chemically diverse, biologically active natural products, and serves as an invaluable resource in the ongoing search for novel antimicrobial compounds. Recent advances in extraction and isolation techniques, and in state-of-the-art technologies involved in organic synthesis and chemical structure elucidation, have accelerated the numbers of antimicrobial molecules originating from the ocean moving into clinical trials. The chemical diversity associated with these marine-derived molecules is immense, varying from simple linear peptides and fatty acids to complex alkaloids, terpenes and polyketides, etc. Such an array of structurally distinct molecules performs functionally diverse biological activities against many pathogenic bacteria and fungi, making marine-derived natural products valuable commodities, particularly in the current age of antimicrobial resistance. In this review, we have highlighted several marine-derived natural products (and their synthetic derivatives), which have gained recognition as effective antimicrobial agents over the past five years (2012–2017). These natural products have been categorized based on their chemical structures and the structure-activity mediated relationships of some of these bioactive molecules have been discussed. Finally, we have provided an insight into how genome mining efforts are likely to expedite the discovery of novel antimicrobial compounds. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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Other

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7 pages, 1127 KiB

Open AccessBrief Report

Discovery of an Unusual Fatty Acid Amide from the ndgR_yo Gene Mutant of Marine-Derived Streptomyces youssoufiensis

by Jing Hou, Jing Liu, Lu Yang, Zengzhi Liu, Huayue Li, Qian Che, Tianjiao Zhu, Dehai Li and Wenli Li

Mar. Drugs 2019, 17(1), 12; https://doi.org/10.3390/md17010012 - 28 Dec 2018

Cited by 6 | Viewed by 3158

Abstract

NdgR_yo, an IclR-like regulator, was selected as the target gene to activate new secondary metabolites in the marine-derived Streptomyces youssoufiensis OUC6819. Inactivation of the ndgR_yo gene in S. youssoufiensis OUC6819 led to the accumulation of a new fatty acid amide (1), with an unusual 3-amino-butyl acid as the amine component. Moreover, its parent fatty acid (2) was also discovered both in the wild-type and ΔndgR_yo mutant strains, which was for the first time isolated from a natural source. The structures of compounds 1 and 2 were elucidated by combination of LC-MS and NMR spectroscopic analyses. This study demonstrated that the ndgR_yo homologs might serve as a target for new compound activation in Streptomyces strains. Full article

(This article belongs to the Special Issue Genome Mining and Marine Microbial Natural Products)

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