Next Article in Journal
Antitumor Potential of Marine and Freshwater Lectins
Next Article in Special Issue
Halophiles and Their Biomolecules: Recent Advances and Future Applications in Biomedicine
Previous Article in Journal
Proapoptotic Index Evaluation of Two Synthetic Peptides Derived from the Coneshell Californiconus californicus in Lung Cancer Cell Line H1299
Previous Article in Special Issue
Characterization of Carotenoid Biosynthesis in Newly Isolated Deinococcus sp. AJ005 and Investigation of the Effects of Environmental Conditions on Cell Growth and Carotenoid Biosynthesis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Marine Drugs
Volume 18
Issue 1
10.3390/md18010009
marinedrugs-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Deep-Sea Fungi Could Be the New Arsenal for Bioactive Molecules

by
Muhammad Zain ul Arifeen
,
Yu-Nan Ma
,
Ya-Rong Xue
and
Chang-Hong Liu
*
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
*
Author to whom correspondence should be addressed.
Mar. Drugs 2020, 18(1), 9; https://doi.org/10.3390/md18010009
Submission received: 28 November 2019 / Revised: 15 December 2019 / Accepted: 17 December 2019 / Published: 20 December 2019
(This article belongs to the Special Issue Bioactive Molecules from Extreme Environments)
Browse Figures
Versions Notes

Abstract

:
Growing microbial resistance to existing drugs and the search for new natural products of pharmaceutical importance have forced researchers to investigate unexplored environments, such as extreme ecosystems. The deep-sea (>1000 m below water surface) has a variety of extreme environments, such as deep-sea sediments, hydrothermal vents, and deep-sea cold region, which are considered to be new arsenals of natural products. Organisms living in the extreme environments of the deep-sea encounter harsh conditions, such as high salinity, extreme pH, absence of sun light, low temperature and oxygen, high hydrostatic pressure, and low availability of growth nutrients. The production of secondary metabolites is one of the strategies these organisms use to survive in such harsh conditions. Fungi growing in such extreme environments produce unique secondary metabolites for defense and communication, some of which also have clinical significance. Despite being the producer of many important bioactive molecules, deep-sea fungi have not been explored thoroughly. Here, we made a brief review of the structure, biological activity, and distribution of secondary metabolites produced by deep-sea fungi in the last five years.

1. Deep-Sea Fungi: A Novel Source of Bioactive Molecules

Antibiotics and antifungal drugs are the most commonly used drugs in the world, but their role in treating human diseases has been greatly reduced due to the development of pathogen resistance against these drugs. Scientists are now looking for new, untapped and renewable resources for the isolation of novel compounds to with clinical importance. Despite the fact that the ocean provides habitats to a huge number of microbes, both fungi and bacteria for thousands of years, the microbes of these extreme ecosystems and their potential for new drug discovery have not yet been fully realized due to methodological and technical limitations. Fungi are the most diverse and abundant eukaryotic organisms on the planet, and their presence in all possible extreme ecosystems make them an ideal source for investigations of new drug development. Scientists are interested in the extraction of novel and unique natural products, having clinical importance, from different organisms living in the extreme environments. In addition to terrestrial extreme environments, the ocean could also be considered a good reservoir of bioactive metabolites [1,2,3,4]. Fungi living in the deep-sea environments are known to produce novel bioactive compounds. Although, it is not fully understood why the fungi living in the extreme environments produce unique and novel products, it is assumed that fungal genome has evolved to make necessary adjustments in order to sustain life in such harsh conditions and might be involved in chemical defense and communication [5].
The ocean is considered to be one of the most diverse ecosystems. Compared to terrestrial and coastal ecosystems, the deep-sea (water depths below 1000 m) has a variety of extreme environments, such as temperatures ranging from 0 to 400 °C, lack of light and oxygen, high hydrostatic pressure up to 400 atm, and limited supply of nutrient substrates, making these habitats extremely difficult for life [6,7]. In order to inhabit such extreme ecosystems, organisms should have the potential to adjust to these conditions with different mechanism, such as regulating temperature, pH, and solute concentration, as well as the production of biomolecules to control DNA, protein, and lipid damage. This may be why microorganisms growing in these environments produce special metabolites.
Previously, drug investigators mainly considered bacteria, especially actinomycetes, as an important source of antifungal and antibacterial drugs. Cephalosporin C was the first compound derived from the marine fungus Cephalosporium sp. in 1949. After that, a number of important drugs— for instance, polyketide griseofulvin, terpenoid fusidic acid, cephalosporins, etc.—have been isolated from the marine fungi. Despite being the source of such important products, deep-sea fungi have not received full attention [8]. With the increasing demand for new drugs, scientists are now looking for new and unexplored resources for bioactive compounds, and the deep-sea consists of some extreme ecosystems that are worth exploring for new metabolites. Studies about isolating new bioactive molecules from marine environments are growing at an increasing rate, and hundreds of new compounds are reported every year; for instance, in 2017, a total of 448 new compounds were reported [9].
In this review, we present an overview of all those new and important bioactive metabolites isolated from deep-sea fungi during the last five years. We include only those molecules which were extracted from the deep-sea fungi associated with some kind of extreme environments, irrespective of its isolation from terrestrial counterparts, while all those compounds were excluded which were isolated from marine fungi and were not associated with extreme environments. This review will benefit all those who are interested in extreme-marine-environment fungi and their bioactive molecules. For more detailed information about other important secondary metabolites extracted from marine fungi, one should refer to our previous review papers [10,11,12].

2. Bioactive Compounds from Deep-Sea Fungi

According to the literature survey, we found 151 novel bioactive compounds isolated from marine fungi extracted from different extreme environments in the last five years. The majority of these compounds were isolated from two fungal genera i.e., Penicillium (63, 41.2% of the total compounds) and Aspergillus (43, 28.1% of the total compounds). Table 1 lists the detail of these compounds, which fall into different categories according to their structure.

2.1. Polyketide Compounds

Twenty-four polyketide compounds (1–24; Figure 1) with important biological activities were isolated from fungi extracted from different deep-sea environments. Among them, compounds 1 and 2 were isolated from Penicillium spp., which showed antibiotic activity (MIC of 32 μg/mL against Bacillus subtilis) and nuclear factor NF-kB inhibition activity, respectively [13,14]. Compounds 3–11 were from Aspergillus sp. 16-02-1, which exhibited cytotoxicity (with a 10%–80% inhibition rate at 100 μg/mL against various cancer cell lines i.e., K562, HL-60, HeLa, and BGC-823) [15]. Similarly, compounds 12–24 were isolated from the species belonging to Ascomycetes, Engyodontium, and Lindgomycetaceae, out of which compounds 12–13 and 23–24 showed strong antibiotic activities against Bacillus subtilis, Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, and Propionibacterium acnes, while compounds 14–22 exhibited strong cytotoxic activity (IC50 4.9 µM) against U937 cells (Table 1) [16,17,18].

2.2. Nitrogen-Containing Compounds

Twenty-four novel alkaloid-bioactive compounds (25–48; Figure 2) have been reported from deep-sea fungi since 2013, out of which compounds 25–40 were isolated from Penicillium spp., and showed cytotoxic activities against BV2 cell (IC50 of 27–45 µg/mL), brine shrimp (IC50 of 14.1 to 38.5 µg/mL), SMMC-7721 (IC50 of 54.2 µM), BEL-7402 ((IC50 of 17.5 µM), and BEL-7402 (IC50 of 19.8 µM) [19,20,21]. Compounds 41–46 were identified from Aspergillus spp., in which compounds 41 and 45–46 displayed antibiotic activity (MIC of 30 to 40 µg/mL) against BCG, Candida albicans, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus cereus, Klebsiella pneumoniae, and Escherichia coli, while compounds 47 and 48 were extracted from other genera and showed antimicrobial activity (MIC between 16 and 64 µg/mL against Escherichia coli, Aeromonas hydrophila, Micrococcus luteus, Staphylococcus aureus, Vibrio anguillarum, Vibrio harveyi, and Vibrio parahaemolyticus) and cytotoxic activity against human cervical carcinoma HeLa, respectively [22,23,24,25,26].

2.3. Polypeptides

Twenty-two polypeptides with novel structures (49–70; Figure 3) were reported from fungi inhabiting different marine environments during 2013–2019. Compounds 49 and 50 were isolated from Penicillium canescens and displayed antibiotic activity against Bacillus amyloliquefaciens and Pseudomonas aeruginosa at 100 µM, while compounds 51–55 were extracted from Aspergillus spp., in which 51–54 showed cytotoxic activity (IC50 of 15–25 μg/mL) against HepG2, SMMC-7721, Bel-7402, and human glioma U87 cell lines, while compound 55 showed inhibitory effects (IC50 value of 5.11 μmol/L) against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) [27,28,29,30]. However, compounds 56–64, which were obtained from Simplicillium obclavatum, and 65–70, obtained from Trichoderma asperellum, displayed cytotoxicity (IC50 of 39.4–100 µM) against human leukemia HL-60 and K562 cell lines and antibiotic activity (IC50 of 39.4–100 µM) against Gram-positive bacteria (e.g., Bacillus amyloliquefaciens, Staphylococcus aureus) and Gram-negative bacteria (e.g., Pseudomonas aeruginosa and Escherichia coli), respectively [28,31].

2.4. Ester and Phenolic Derivatives

Six new ester derivatives (71–76; Figure 4) were extracted from Aspergillus ungui NKH-007 and showed inhibition of sterol O-acyltransferase (SOAT) enzymes in Chinese hamster ovary (CHO) cells and are thus considered to be good candidates for an anti-atherosclerotic agent [32]. Five new phenolic compounds (77–81; Figure 4) isolated from Penicillium sp. and Aspergillus versicolor showed potent activity against Staphylococcus aureus and Bacillus subtilis, with MIC values of 2–8 μg/mL [33,34]. However, compounds 78–81 expressed antiviral activity toward HSV-1, with EC50 values of 3.12–6.25 μM [34].

2.5. Piperazine Derivatives

Fourteen new piperazine derivatives (82–95; Figure 5) reported from marine fungi during the last five years. These derivatives were isolated from genera of Penicillium, Aspergillus, and Dichotomomyces collected from deep-sea sediments. Compounds 82–84 showed strong cytotoxicity with IC50 of 1.7 and 2 µM against K562 and mouse lymphoma cell line, respectively; similarly, compounds 91–95 also showed strong cytotoxic activity [35,36,37]. Compounds 85–89 showed antibacterial activity against Staphylococcus aureus with the MIC values of 6.25–12.5 µg/mL [21]. The new compound 90 also showed stronger inhibition activity against α-glucosidase with IC50 value of 138 µM [37].

2.6. Terpenoid Compounds

Thirty-six new and important bioactive terpenoids (96–131; Figure 6) have been isolated from marine fungi extracted from the deep-sea sediments since 2013. Compounds 96–113 were isolated from Penicillium spp., while compounds 114–131 were extracted from Aspergillus spp. Breviones (96–99), isolated from the deepest sediment-derived fungus Penicillium sp. (5115 m depth), displayed diverse activities, such as cytotoxicity against HeLa, MCF-7, and A549 cells with IC50 values of 7.44 to 32.5 µM, respectively, and growth inhibition of HIV-1 with EC50 value of 14.7 µM against C8166 cells [22,38]. Compounds 100–110 showed antibiotic and inhibition activities against silkworm, while 20-nor-isopimarane diterpenoids, including aspewentins (114–118), asperethers (121–125), asperoloids (119–120), and compounds 130 and 131, showed cytotoxic activities [33,39,40,41,42,43,44,45]. However, the spirocyclic diterpenes (111–113) exhibited strong anti-allergic effect with 18% inhibition at 20 μg/mL [46]. Interestingly, four new compounds (126–129) were extracted from hydrothermal vent-derived Aspergillus sydowii, through activation of a new pathway for secondary metabolite production by the addition of a 5-azacytidine (a DNA methyltransferase inhibitor). These compounds showed anti-inflammatory and antidiabetic activities and are thus the first secondary metabolites isolated from fungi which have both antidiabetic and anti-inflammatory activities [47].

2.7. Other Unrelated Compounds

Twenty secondary metabolites with different structures were isolated from deep-sea fungi, mainly from Penicillium spp. and Aspergillus spp. (132–151; Figure 7). Penipacids A–F (134–139), polyoxygenated sterol (132), dicitrinone B (133) and butanolide A (140), which were isolated from deep-sea sediments-derived Penicillium spp., showed cytotoxic activities against RKO, MCF-7, PTP1B and A375 cancer cell lines with IC50 values of 8.4–28.4 µM [38,42,48,49]. Similarly, four isocoumarins, penicillisocoumarin A–D (147–150), and an isocoumarins aspergillumarin B (151) were also isolated from Penicillium which showed weak antibacterial activities [33]. Four antibiotic cyclopenin derivatives compounds (141–144) and a series of antitumor wentilactones (145,146) were isolated from Aspergillus spp. [50,51].

3. Conclusions and Perspective

The results of current studies indicate that the deep-sea extreme environmental fungi are one of the rich and unexploited sources of important medicinal lead compounds. Most of the fungi (e.g., Penicillium spp. and Aspergillus spp.) living in the extreme environments of the deep-sea have the potential to synthesize new bioactive compounds. However, the research on deep-sea fungi and their metabolites is very limited due to the difficulty of sampling and the limitation of culture technology. Thanks to the advances in genome technology and the implementation of the deep-sea drilling program, novel compounds with great biological activities are expected from these fungi in the near future. From the literature review, we can say these fungi from the extreme environments have the potential to produce clinically important natural products. The compounds we discussed in this review show strong bioactivities and might have the potential to be a future anticancer drug. Among them, terpenoid derivatives were the most important and abundant compound category which were mainly isolated from deep-sea derived Penicillium spp. and Aspergillus spp. This class of compounds showed strongest antibiotic and cytotoxic activities as compared to other classes of compounds and has the potential to be a future candidate for anticancer drugs, especially brevione, which was isolated from the deepest part of the sea and showed the strongest cytotoxic activity.

Author Contributions

Writing—original draft preparation, M.Z.u.A.; writing—review and editing, Y.-N.M., Y.-R.X. and C.-H.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the National Natural Science Foundation of China (General Program: 41773083, 41973073; Major Program: 91951121).

Conflicts of Interest

The authors declare that they have no competing interests.

References

  1. König, G.M.; Kehraus, S.; Seibert, S.F.; Abdel-Lateff, A.; Müller, D. Natural products from marine organisms and their associated microbes. Chem. Bio. Chem. 2006, 7, 229–238. [Google Scholar] [CrossRef] [PubMed]
  2. Chen, G.; Wang, H.-F.; Pei, Y.-H. Secondary metabolites from marine-derived microorganisms. J. Asian Nat. Prod. Res. 2014, 16, 105–122. [Google Scholar] [CrossRef] [PubMed]
  3. Agrawal, S.; Adholeya, A.; Deshmukh, S.K. The pharmacological potential of non-ribosomal peptides from marine sponge and tunicates. Front. Pharmacol. 2016, 7, 333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Deshmukh, S.K.; Prakash, V.; Ranjan, N. Recent advances in the discovery of bioactive metabolites from Pestalotiopsis. Phytochem. Rev. 2017, 16, 883–920. [Google Scholar] [CrossRef]
  5. Deshmukh, S.K.; Prakash, V.; Ranjan, N. Marine fungi: A source of potential anticancer compounds. Front. Microbiol. 2018, 8, 2536. [Google Scholar] [CrossRef]
  6. Danovaro, R.; Corinaldesi, C.; Dell’Anno, A.; Snelgrove, P.V. The deep-sea under global change. Curr. Biol. 2017, 27, R461–R465. [Google Scholar] [CrossRef] [Green Version]
  7. Barone, G.; Varrella, S.; Tangherlini, M.; Rastelli, E.; Dell’Anno, A.; Danovaro, R.; Corinaldesi, C. Marine fungi: Biotechnological perspectives from deep-hypersaline anoxic basins. Diversity 2019, 11, 113. [Google Scholar] [CrossRef] [Green Version]
  8. Hamilton-Miller, J. Development of the semi-synthetic penicillins and cephalosporins. Int. J. Antimicrob. 2008, 31, 189–192. [Google Scholar] [CrossRef]
  9. Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2019, 36, 122–173. [Google Scholar] [CrossRef] [Green Version]
  10. Wang, Y.-T.; Xue, Y.-R.; Liu, C.-H. A brief review of bioactive metabolites derived from deep-sea fungi. Mar. Drugs 2015, 13, 4594–4616. [Google Scholar] [CrossRef] [Green Version]
  11. Arifeen, M.Z.U.; Liu, C.-H. Novel enzymes isolated from marine-derived fungi and its potential applications. United J. Biochem. Biotechnol. 2018, 1, 1–11. [Google Scholar]
  12. Arifeen, M.Z.U.; Xue, Y.-R.; Liu, C.-H. Deep-sea fungi: Diversity, enzymes, and bioactive metabolites. In Fungi in Extreme Environments: Ecological Role and Biotechnological Significance; Springer: Berlin, Germany, 2019; pp. 331–347. [Google Scholar]
  13. Pan, C.; Shi, Y.; Auckloo, B.; Chen, X.; Chen, C.-T.; Tao, X.; Wu, B. An unusual conformational isomer of verrucosidin backbone from a hydrothermal vent fungus, Penicillium sp. Y-50-10. Mar. Drugs 2016, 14, 156. [Google Scholar] [CrossRef] [Green Version]
  14. Wu, G.; Ma, H.; Zhu, T.; Li, J.; Gu, Q.; Li, D. Penilactones A and B, two novel polyketides from Antarctic deep-sea derived fungus Penicillium crustosum PRB-2. Tetrahedron 2012, 68, 9745–9749. [Google Scholar] [CrossRef]
  15. Chen, X.-W.; Li, C.-W.; Cui, C.-B.; Hua, W.; Zhu, T.-J.; Gu, Q.-Q. Nine new and five known polyketides derived from a deep sea-sourced Aspergillus sp. 16-02-1. Mar. Drugs 2014, 12, 3116–3137. [Google Scholar] [CrossRef] [Green Version]
  16. Tian, Y.-Q.; Lin, X.-P.; Liu, J.; Kaliyaperumal, K.; Ai, W.; Ju, Z.-R.; Yang, B.; Wang, J.; Yang, X.-W.; Liu, Y. Ascomycotin A, a new citromycetin analogue produced by Ascomycota sp. Ind19F07 isolated from deep sea sediment. Nat. Prod. Res. 2015, 29, 820–826. [Google Scholar] [CrossRef]
  17. Wu, B.; Wiese, J.; Labes, A.; Kramer, A.; Schmaljohann, R.; Imhoff, J. Lindgomycin, an unusual antibiotic polyketide from a marine fungus of the Lindgomycetaceae. Mar. Drugs 2015, 13, 4617–4632. [Google Scholar] [CrossRef] [Green Version]
  18. Yao, Q.; Wang, J.; Zhang, X.; Nong, X.; Xu, X.; Qi, S. Cytotoxic polyketides from the deep-sea-derived fungus Engyodontium album DFFSCS021. Mar. Drugs 2014, 12, 5902–5915. [Google Scholar] [CrossRef] [Green Version]
  19. Cardoso-Martínez, F.; de la Rosa, J.M.; Díaz-Marrero, A.R.; Darias, J.; D’Croz, L.; Cerella, C.; Diederich, M.; Cueto, M. Oximoaspergillimide, a fungal derivative from a marine isolate of Aspergillus sp. Eur. J. Org. Chem. 2015, 2015, 2256–2261. [Google Scholar] [CrossRef]
  20. Fredimoses, M.; Zhou, X.; Ai, W.; Tian, X.; Yang, B.; Lin, X.; Xian, J.-Y.; Liu, Y. Westerdijkin A, a new hydroxyphenylacetic acid derivative from deep sea fungus Aspergillus westerdijkiae SCSIO 05233. Nat. Prod. Res. 2015, 29, 158–162. [Google Scholar] [CrossRef]
  21. Hu, J.; Li, Z.; Gao, J.; He, H.; Dai, H.; Xia, X.; Liu, C.; Zhang, L.; Song, F. New diketopiperazines from a marine-derived fungus strain Aspergillus versicolor MF180151. Mar. Drugs 2019, 17, 262. [Google Scholar] [CrossRef] [Green Version]
  22. Zhang, X.; Li, S.-J.; Li, J.-J.; Liang, Z.-Z.; Zhao, C.-Q. Novel natural products from extremophilic fungi. Mar. Drugs 2018, 16, 194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Li, C.-S.; An, C.-Y.; Li, X.-M.; Gao, S.-S.; Cui, C.-M.; Sun, H.-F.; Wang, B.-G. Triazole and dihydroimidazole alkaloids from the marine sediment-derived fungus Penicillium paneum SD-44. J. Nat. Prod. 2011, 74, 1331–1334. [Google Scholar] [CrossRef] [PubMed]
  24. Xu, X.; Zhang, X.; Nong, X.; Wei, X.; Qi, S. Oxindole alkaloids from the fungus Penicillium commune DFFSCS026 isolated from deep-sea-derived sediments. Tetrahedron 2015, 71, 610–615. [Google Scholar] [CrossRef]
  25. Wijesekara, I.; Li, Y.-X.; Vo, T.-S.; Van Ta, Q.; Ngo, D.-H.; Kim, S.-K. Induction of apoptosis in human cervical carcinoma HeLa cells by neoechinulin A from marine-derived fungus Microsporum sp. Process Biochem. 2013, 48, 68–72. [Google Scholar] [CrossRef]
  26. Zhang, P.; Mandi, A.; Li, X.-M.; Du, F.-Y.; Wang, J.-N.; Li, X.; Kurtan, T.; Wang, B.-G. Varioxepine A, a 3 H-oxepine-containing alkaloid with a new oxa-cage from the marine algal-derived endophytic fungus Paecilomyces variotii. Org. Lett. 2014, 16, 4834–4837. [Google Scholar] [CrossRef]
  27. Dasanayaka, S.; Nong, X.-H.; Liang, X.; Liang, J.-Q.; Amin, M.; Qi, S.-H. New dibenzodioxocinone and pyran-3, 5-dione derivatives from the deep-sea-derived fungus Penicillium canescens SCSIO z053. J. Asian Nat. Prod. Res. 2019, 1–8. [Google Scholar] [CrossRef]
  28. Ren, J.; Xue, C.; Tian, L.; Xu, M.; Chen, J.; Deng, Z.; Proksch, P.; Lin, W. Asperelines A− F, peptaibols from the marine-derived fungus Trichoderma asperellum. J. Nat. Prod. 2009, 72, 1036–1044. [Google Scholar] [CrossRef]
  29. Jiang, W.; Ye, P.; Chen, C.-T.; Wang, K.; Liu, P.; He, S.; Wu, X.; Gan, L.; Ye, Y.; Wu, B. Two novel hepatocellular carcinoma cycle inhibitory cyclodepsipeptides from a hydrothermal vent crab-associated fungus Aspergillus clavatus C2WU. Mar. Drugs 2013, 11, 4761–4772. [Google Scholar] [CrossRef]
  30. Luo, X.W.; Yun, L.; Liu, Y.J.; Zhou, X.F.; Liu, Y.H. Peptides and polyketides isolated from the marine sponge-derived fungus Aspergillus terreus SCSIO 41008. Chin. J. Nat. Med. 2019, 17, 149–154. [Google Scholar] [CrossRef]
  31. Liang, X.; Zhang, X.-Y.; Nong, X.-H.; Wang, J.; Huang, Z.-H.; Qi, S.-H. Eight linear peptides from the deep-sea-derived fungus Simplicillium obclavatum EIODSF 020. Tetrahedron 2016, 72, 3092–3097. [Google Scholar] [CrossRef]
  32. Uchida, R.; Nakajyo, K.; Kobayashi, K.; Ohshiro, T.; Terahara, T.; Imada, C.; Tomoda, H. 7-Chlorofolipastatin, an inhibitor of sterol O-acyltransferase, produced by marine-derived Aspergillus ungui NKH-007. J. Antibiot. 2016, 69, 647. [Google Scholar] [CrossRef] [PubMed]
  33. Pan, C.; Shi, Y.; Auckloo, B.N.; ul Hassan, S.S.; Akhter, N.; Wang, K.; Ye, Y.; Chen, C.-T.A.; Tao, X.; Wu, B. Isolation and antibiotic screening of fungi from a hydrothermal vent site and characterization of secondary metabolites from a Penicillium isolate. Mar. Biotechnol. 2017, 19, 469–479. [Google Scholar] [CrossRef] [PubMed]
  34. Huang, Z.; Nong, X.; Ren, Z.; Wang, J.; Zhang, X.; Qi, S. Anti-HSV-1, antioxidant and antifouling phenolic compounds from the deep-sea-derived fungus Aspergillus versicolor SCSIO 41502. Bioorg. Med. Chem. Lett. 2017, 27, 787–791. [Google Scholar] [CrossRef] [PubMed]
  35. Liu, C.-C.; Zhang, Z.-Z.; Feng, Y.-Y.; Gu, Q.-Q.; Li, D.-H.; Zhu, T.-J. Secondary metabolites from Antarctic marine-derived fungus Penicillium crustosum HDN153086. Nat. Prod. Res. 2019, 33, 414–419. [Google Scholar] [CrossRef] [PubMed]
  36. Orfali, R.S.; Aly, A.H.; Ebrahim, W.; Abdel-Aziz, M.S.; Müller, W.E.; Lin, W.; Daletos, G.; Proksch, P. Pretrichodermamide C and N-methylpretrichodermamide B, two new cytotoxic epidithiodiketopiperazines from hyper saline lake derived Penicillium sp. Phytochem. Lett. 2015, 11, 168–172. [Google Scholar] [CrossRef]
  37. Fan, Z.; Sun, Z.-H.; Liu, Z.; Chen, Y.-C.; Liu, H.-X.; Li, H.-H.; Zhang, W.-M. Dichotocejpins A–C: New diketopiperazines from a deep-sea-derived fungus Dichotomomyces cejpii FS110. Mar. Drugs 2016, 14, 164. [Google Scholar] [CrossRef] [Green Version]
  38. Li, Y.; Ye, D.; Shao, Z.; Cui, C.; Che, Y. A sterol and spiroditerpenoids from a Penicillium sp. isolated from a deep sea sediment sample. Mar. Drugs 2012, 10, 497–508. [Google Scholar] [CrossRef]
  39. Li, X.-D.; Li, X.-M.; Li, X.; Xu, G.-M.; Liu, Y.; Wang, B.-G. Aspewentins D–H, 20-nor-isopimarane derivatives from the deep sea sediment-derived fungus Aspergillus wentii SD-310. J. Nat. Prod. 2016, 79, 1347–1353. [Google Scholar] [CrossRef]
  40. Wu, G.; Lin, A.; Gu, Q.; Zhu, T.; Li, D. Four new chloro-eremophilane sesquiterpenes from an Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1. Mar. Drugs 2013, 11, 1399–1408. [Google Scholar] [CrossRef] [Green Version]
  41. Lin, A.; Wu, G.; Gu, Q.; Zhu, T.; Li, D. New eremophilane-type sesquiterpenes from an antarctic deep-sea derived fungus, Penicillium sp. PR19 N-1. Arch. Pharm. Res. 2014, 37, 839–844. [Google Scholar] [CrossRef]
  42. Zhou, Y.; Li, Y.-H.; Yu, H.-B.; Liu, X.-Y.; Lu, X.-L.; Jiao, B.-H. Furanone derivative and sesquiterpene from antarctic marine-derived fungus Penicillium sp. S-1-18. J. Asian Nat. Prod. Res. 2018, 20, 1108–1115. [Google Scholar] [CrossRef] [PubMed]
  43. Li, X.-D.; Li, X.; Li, X.-M.; Xu, G.-M.; Zhang, P.; Meng, L.-H.; Wang, B.-G. Tetranorlabdane diterpenoids from the deep sea sediment-derived fungus Aspergillus wentii SD-310. Planta Med. 2016, 82, 877–881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Li, X.; Li, X.-M.; Li, X.-D.; Xu, G.-M.; Liu, Y.; Wang, B.-G. 20-Nor-isopimarane cycloethers from the deep-sea sediment-derived fungus Aspergillus wentii SD-310. RSC Adv. 2016, 6, 75981–75987. [Google Scholar] [CrossRef]
  45. Fang, W.; Lin, X.; Zhou, X.; Wan, J.; Lu, X.; Yang, B.; Ai, W.; Lin, J.; Zhang, T.; Tu, Z. Cytotoxic and antiviral nitrobenzoyl sesquiterpenoids from the marine-derived fungus Aspergillus ochraceus Jcma1F17. MedChemComm 2014, 5, 701–705. [Google Scholar] [CrossRef]
  46. Niu, S.; Fan, Z.-W.; Xie, C.-L.; Liu, Q.; Luo, Z.-H.; Liu, G.; Yang, X.-W. Spirograterpene A, a tetracyclic spiro-diterpene with a fused 5/5/5/5 ring system from the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475. J. Nat. Prod. 2017, 80, 2174–2177. [Google Scholar] [CrossRef]
  47. Chung, Y.-M.; Wei, C.-K.; Chuang, D.-W.; El-Shazly, M.; Hsieh, C.-T.; Asai, T.; Oshima, Y.; Hsieh, T.-J.; Hwang, T.-L.; Wu, Y.-C. An epigenetic modifier enhances the production of anti-diabetic and anti-inflammatory sesquiterpenoids from Aspergillus sydowii. Bioorg. Med. Chem. 2013, 21, 3866–3872. [Google Scholar] [CrossRef]
  48. Li, C.-S.; Li, X.-M.; Gao, S.-S.; Lu, Y.-H.; Wang, B.-G. Cytotoxic anthranilic acid derivatives from deep sea sediment-derived fungus Penicillium paneum SD-44. Mar. Drugs 2013, 11, 3068–3076. [Google Scholar] [CrossRef]
  49. Chen, L.; Gong, M.-W.; Peng, Z.-F.; Zhou, T.; Ying, M.-G.; Zheng, Q.-H.; Liu, Q.-Y.; Zhang, Q.-Q. The marine fungal metabolite, dicitrinone B, induces A375 cell apoptosis through the ROS-related caspase pathway. Mar. Drugs 2014, 12, 1939–1958. [Google Scholar] [CrossRef] [Green Version]
  50. Pan, C.; Shi, Y.; Chen, X.; Chen, C.-T.A.; Tao, X.; Wu, B. New compounds from a hydrothermal vent crab-associated fungus Aspergillus versicolor XZ-4. Org. Biomol. Chem. 2017, 15, 1155–1163. [Google Scholar] [CrossRef]
  51. Xu, R.; Xu, G.-M.; Li, X.-M.; Li, C.-S.; Wang, B.-G. Characterization of a newly isolated marine fungus Aspergillus dimorphicus for optimized production of the anti-tumor agent wentilactones. Mar. Drugs 2015, 13, 7040–7054. [Google Scholar] [CrossRef]
Marinedrugs 18 00009 g001 550
Figure 1. Structures of polyketide secondary metabolites obtained from deep-sea fungi.
Figure 1. Structures of polyketide secondary metabolites obtained from deep-sea fungi.
Marinedrugs 18 00009 g001
Marinedrugs 18 00009 g002 550
Figure 2. Bioactive alkaloid compounds isolated from deep-sea fungi.
Figure 2. Bioactive alkaloid compounds isolated from deep-sea fungi.
Marinedrugs 18 00009 g002
Marinedrugs 18 00009 g003a 550Marinedrugs 18 00009 g003b 550
Figure 3. Bioactive polypeptides isolated from deep-sea fungi.
Figure 3. Bioactive polypeptides isolated from deep-sea fungi.
Marinedrugs 18 00009 g003aMarinedrugs 18 00009 g003b
Marinedrugs 18 00009 g004 550
Figure 4. Ester and phenolic derivatives obtained from deep-sea fungi.
Figure 4. Ester and phenolic derivatives obtained from deep-sea fungi.
Marinedrugs 18 00009 g004
Marinedrugs 18 00009 g005 550
Figure 5. Piperazine derivatives isolated from deep-sea fungi.
Figure 5. Piperazine derivatives isolated from deep-sea fungi.
Marinedrugs 18 00009 g005
Marinedrugs 18 00009 g006 550
Figure 6. Structures of terpenoid secondary metabolites obtained from deep-sea fungi.
Figure 6. Structures of terpenoid secondary metabolites obtained from deep-sea fungi.
Marinedrugs 18 00009 g006
Marinedrugs 18 00009 g007 550
Figure 7. Bioactive metabolites derived from deep-sea fungi.
Figure 7. Bioactive metabolites derived from deep-sea fungi.
Marinedrugs 18 00009 g007
Table
Table 1. Secondary metabolites extracted from deep-sea fungi during 2013–2019.
Table 1. Secondary metabolites extracted from deep-sea fungi during 2013–2019.
MetabolitesFungal SpeciesSourceLocationDepth (m) *Bioactivity Ref.
Polyketide
Methyl-isoverrucosidinol (1)Penicillium sp. Y-50-10Sulfur-rich Sedimenthydrothermal vent, Taiwan_Antibiotic [13]
Penilactone A (2)Penicillium crustosum PRB-2SedimentPrydz Bay, Antarctica526NF-kB inhibition[14]
Aspiketolactonol (3)
Aspilactonols A–F (4-9)
Aspyronol (10)
Epiaspinonediol (11)		Aspergillus sp. 16-02-1Hydrothermal vent waterLau Basin, Southwest Pacific Ocean,2255Cytotoxic [15]
Ascomycotin A (12)
Diorcinol (13)		Ascomycota sp. Ind19F07SedimentIndian Ocean3614Antibiotic[16]
Engyodontiumones A–J (14-22)Engyodontium album DFFSCS021SedimentSouth China Sea3739Cytotoxic[18]
Lindgomycin (23)
Ascosetin (24)		Lindgomycetaceae strains KF970 and LF327SedimentGreenland Sea, Baltic Sea3650Antibiotic [17]
Nitrogen-containing compounds
Brevicompanines D–H (25-29)Penicillium sp. F1Sediment_5080LPS-induced inflammation [22]
Cyclopiamide B–J (30-38)Penicillium commune DFFSCS026SedimentSouth China Sea3563Cytotoxic [24]
Penipanoid A (39)
Quinazolinone (40)		Penicillium paneum SD-44SedimentSouth China Sea201Cytotoxic[23]
(±) Brevianamide R (41)Aspergillus
versicolor MF180151		SedimentBohai Sea, China_Antibacterial [21]
Circumdatin F and G (42-43)Aspergillus westerdijkiae SCSIO 05233SedimentSouth China Sea4593Cytotoxic[20]
Oximoaspergillimide (44)
Neohydroxyaspergillic (45)
Neoaspergillic (46)		Aspergillus sp. (CF07002)WaterPacific Ocean off the coast of Panama Cytotoxic
Antibiotic 		[19]
Varioxepine A (47)Paecilomyces variotii EN-291Deep sea water__Antibiotic [26]
Neoechinulin A (48) Microsporum sp. (MFS-YL)Red algaGuryongpo, Korea_Cytotoxic[25]
Polypeptide
Canescenin A and B (49-50) Penicillium canescens SCSIO z053WaterEast China Sea2013Antibacterial [27]
Clavatustide A and B (51-52)Aspergillus clavatus C2WUHydrothermal vent crab Taiwan Kueishantao_Cytotoxic [29]
Aspergillamides C and D (53-54)
Butyrolactone I (55)		Aspergillus terreus SCSIO 41008Sponge Guangdong, China_Cytotoxic
Antibiotic 		[30]
Simplicilliumtides A–I (56-64)Simplicillium obclavatum EIODSF 020SedimentEast Indian Ocean4571Cytotoxic [31]
Asperelines A–F (65-70)Trichoderma asperellumSediment Antarctic Penguin Island_Antibiotic [28]
Esters
7-chlorofolipastatin (71)
Folipostatin B (72)
Unguinol (73)
2-chlorounginol (74)
2,7-dichlorounguinol (75)
Nornidulin (76)		Aspergillus ungui NKH-007SedimentSuruga Bay, Japan_Anti-atherosclerotic
Cytotoxic
Antibiotic 		[32]
Phenolic
Pestalotionol (77)Penicillium sp. Y-5-2Hydrothermal vent waterKueishantao off Taiwan_Antibiotic[33]
Aspergilol G–I (78-80)
Coccoquinone A (81) 		Aspergillus versicolor SCSIO 41502SedimentSouth China Sea2326Anti-HSV-1
Antioxidant
Antifouling		[34]
Piperazine
Fusaperazine F (82)Penicillium crustosum HDN153086Sediment Prydz Bay, Antarctica_Cytotoxic[35]
N-methyl-pretrichodermamide B (83)
Pretrichodermamide C (84)		Penicillium sp. (WN-11-1-3-1-2)Hypersaline sediment Wadi El-Natrun, Egypt_Cytotoxic[36]
(±) 7,8-epoxy-brevianamide Q (85)
(±) 8-hydroxy-brevianamide R (86)
(±) 8-epihydroxy-brevianamide R (87)
Brevianamide R (88)
Versicolorin B (89)		Aspergillus versicolor MF180151SedimentBohai Sea, China_Antibiotic [21]
Dichotocejpins A (90)
6-deoxy-5a,6-didehydrogliotoxin (91)
Gliotoxin (92)
Acetylgliotoxin (93)
6-acetylbis(methylthio)-gliotoxin (94)
1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino [1,2-a] indole (95)		Dichotomomyces cejpii FS110SedimentSouth China Sea3941α-Glucosidase inhibition
Cytotoxic		[37]
Terpenoid
Brevione F–I (96-99)Penicillium sp. (MCCC 3A00005)SedimentPacific Ocean5115Cytotoxic
HIV-1 inhibition 		[22,38]
Dehydroaustin (100)
Dehydroaustinol (101)
7-hydroxydehydroaustin (102)
Austinone (103)
Austinol (104)
Austin (105)
Austinolide (106)		Penicillium sp. Y-5-2Hydrothermal vent waterKueishantao off Taiwan8Antibacterial
Anti-insectal 		[33]
1-chloro-3β-acetoxy-7-hydroxytrinoreremophil-1,6,9-trien-8-one (107)
Eremophilane-type sesquiterpenes (108)
Eremofortine C (109)		Penicillium sp. PR19N-1Sediment Prydz Bay, Antarctica526Cytotoxic[40,41]
Guignarderemophilane F (110)Penicillium sp. S-1-18SedimentAntarctic1393Antibacterial [42]
Spirograterpene A (111)
Conidiogenone C and I (112-113)		Penicillium granulatum MCCC 3A00475WaterPrydz Bay of Antarctica2284Antiallergic [46]
Aspewentin A and D–H (114-118)
Asperethers A–E (121-125)
Asperolides D and E (119-120) 		Aspergillus wentii SD-310SedimentSouth China Sea2038Antimicrobial
Cytotoxic
Anti-inflammatory 		[39,43,44]
(7S)-(+)7-O-methylsydonol (126)
(7S,11S)-(+)-12-hydroxysydonic acid (127)
7-deoxy-7,14-didehydrosydonol (128)
(S)-(+)-sydonol (129)		Aspergillus sydowiiSedimentHsinchu, Taiwan_Anti-inflammatory[47]
6b,9a-dihydroxy-14-p-nitrobenzoylcinnamolide (130)
Insulicolide A (131)		Aspergillus ochraceus Jcma1F17Marine alga Coelarthrum sp.South China Sea_Antiviral
Cytotoxic 		[45]
Other compounds
Sterolic acid (132)Penicillium sp. MCCC 3A00005SedimentEast Pacific Ocean5115Cytotoxic [38]
Dicitrinone B (133) Penicillium citrinumSedimentLangqi Island, Fujian, China_Antitumor [49]
Penipacids A–F (134-139)Penicillium paneum SD-44SedimentSouth China Sea_Cytotoxic [48]
Butanolide A (140)Penicillium sp. S-1-18SedimentAntarctic seabed1393Cytotoxic [42]
7-Methoxycyclopeptin (141)
7-Methoxy dehydro cyclopeptin (142)
7-Methoxy cyclopenin (143)
9-Hydroxy-3-methoxyviridicatin (144) 		Aspergillus versicolor XZ-4Hydrothermal vent crabKueishantao, Taiwan Antibiotic [50]
Wentilactone A and B (145-146)Aspergillus dimorphicus SD317SedimentSouth China Sea2038Antitumor[51]
Penicillisocoumarin A–D (147-150)
Aspergillumarins B (151)		Penicillium sp. Y-5-2Hydrothermal vent waterKueishantao off Taiwan8Antibacterial[33]
* Depth represents water depth below the surface.

Share and Cite

MDPI and ACS Style

Zain ul Arifeen, M.; Ma, Y.-N.; Xue, Y.-R.; Liu, C.-H. Deep-Sea Fungi Could Be the New Arsenal for Bioactive Molecules. Mar. Drugs 2020, 18, 9. https://doi.org/10.3390/md18010009

AMA Style

Zain ul Arifeen M, Ma Y-N, Xue Y-R, Liu C-H. Deep-Sea Fungi Could Be the New Arsenal for Bioactive Molecules. Marine Drugs. 2020; 18(1):9. https://doi.org/10.3390/md18010009

Chicago/Turabian Style

Zain ul Arifeen, Muhammad, Yu-Nan Ma, Ya-Rong Xue, and Chang-Hong Liu. 2020. "Deep-Sea Fungi Could Be the New Arsenal for Bioactive Molecules" Marine Drugs 18, no. 1: 9. https://doi.org/10.3390/md18010009

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop