Genome Mining and Marine Microbial Natural Products

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

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 69762

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Special Issue Editors


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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

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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

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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

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Keywords

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

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Published Papers (11 papers)

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Research

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14 pages, 1879 KiB  
Article
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 26 | Viewed by 4251
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) [...] Read more.
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 16. 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 16 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 15 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  
Article
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 31 | Viewed by 6009
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 [...] Read more.
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  
Article
Biosynthetic Potential of a Novel Antarctic Actinobacterium Marisediminicola antarctica ZS314T 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 - 1 Jul 2019
Cited by 19 | Viewed by 4286
Abstract
Rare actinobacterial species are considered as potential resources of new natural products. Marisediminicola antarctica ZS314T is the only type strain of the novel actinobacterial genus Marisediminicola isolated from intertidal sediments in East Antarctica. The strain ZS314T was able to produce reddish [...] Read more.
Rare actinobacterial species are considered as potential resources of new natural products. Marisediminicola antarctica ZS314T is the only type strain of the novel actinobacterial genus Marisediminicola isolated from intertidal sediments in East Antarctica. The strain ZS314T 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  
Article
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 - 1 Oct 2018
Cited by 21 | Viewed by 4129
Abstract
By treating with histone-deacetylase inhibitor valproate sodium, three new heterdimeric tetrahydroxanthone–chromanone lactones chrysoxanthones A–C (13), 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 [...] Read more.
By treating with histone-deacetylase inhibitor valproate sodium, three new heterdimeric tetrahydroxanthone–chromanone lactones chrysoxanthones A–C (13), 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  
Article
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 18 | Viewed by 4531
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 [...] Read more.
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  
Article
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 34 | Viewed by 6018
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 [...] Read more.
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  
Article
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 33 | Viewed by 7926
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 [...] Read more.
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 (14) and six bacillomycin D analogues (510) 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 110 were assayed for their cytotoxicities against human cancer cell lines HepG2 and MCF7, and the bacillomycin D analogues 710 showed moderate cytotoxicities with IC50 values from 2.9 ± 0.1 to 8.2 ± 0.2 µM. The discovery of 510 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  
Article
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 - 5 Jul 2017
Cited by 22 | Viewed by 5370
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 [...] Read more.
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  
Review
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 5735
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. [...] Read more.
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  
Review
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 110 | Viewed by 16025
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 [...] Read more.
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  
Brief Report
Discovery of an Unusual Fatty Acid Amide from the ndgRyo 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 7 | Viewed by 3541
Abstract
NdgRyo, 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 ndgRyo gene in S. youssoufiensis OUC6819 led to the accumulation of a new fatty acid [...] Read more.
NdgRyo, 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 ndgRyo 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 ΔndgRyo 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 ndgRyo 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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