Metabolites of Marine Sediment-Derived Fungi: Actual Trends of Biological Activity Studies

Marine sediments are characterized by intense degradation of sedimenting organic matter in the water column and near surface sediments, combined with characteristically low temperatures and elevated pressures. Fungi are less represented in the microbial communities of sediments than bacteria and archaea and their relationships are competitive. This results in wide variety of secondary metabolites produced by marine sediment-derived fungi both for environmental adaptation and for interspecies interactions. Earlier marine fungal metabolites were investigated mainly for their antibacterial and antifungal activities, but now also as anticancer and cytoprotective drug candidates. This review aims to describe low-molecular-weight secondary metabolites of marine sediment-derived fungi in the context of their biological activity and covers research articles published between January 2016 and November 2020.


Introduction
MarineÏLsediments are extreme marine environmental conditions reflecting the condition of sea waters as well as coastal areas. A wide variety of inhabitants of marine sediments makes this ecosystem highly competitive, which affects the metabolism of organisms.
Marine sediments are characterized by intense degradation of sedimenting organic matter in the water column and near surface sediments, resulting in recalcitrant organic matter in subsurface layers, combined with characteristically low temperatures and elevated pressures. For a long time, these geophysical conditions were thought to make this area uninhabitable. The perceived low energy supply coupled with geological time scales resulted in the view that most microorganisms in sub seafloor sediments must be either inactive or adapted for extraordinarily low metabolic activity [1]. The revision of the microbiological methods for studying sediments has led to the modern view that the biomass of marine sediments, including deep-sea sediments, can be very significant and have a serious impact on the geological processes of the ocean bottom [2]. The microbial community of bottom sediments includes bacteria and archaea as well as fungi, but the role of the latter in the marine carbon cycle and other biogeochemical process is not yet clear enough [2].
The few studies devoted to a comprehensive estimation of benthic biodiversity, including both prokaryotic and eukaryotic microorganisms, show that fungi (eukaryotic microorganisms) are less represented in the microbial communities of sediments than bacteria and archaea (prokaryotes). A study of microbial communities of coral reefs in the Gulf of Thailand (the South China Sea) showed that relative abundance of fungi in bottom sediments was only 0.017% (avg.), whereas in coral samples it was 25-96 times more [3]. The xanthone derivatives coniochaetone J (4) and epiremisporine B (5) from Penicillium sp. SCSIO Ind16F01 (the Indian Ocean) exhibited weak activity against enterovirus EV71 in vitro, and 5 also was active against influenza A virus subtype H3N2. Moreover, these metabolites have shown cytotoxic effects on the human erythroleukemia K562, human breast MCF-7, and human gastric carcinoma SGC7901 cancer cell lines [16].
A new class of phenolic lactones spiromastilactones A-M was isolated from a deepsea derived fungus Spiromastix sp. (south of the Atlantic Ocean). Most of these compounds exert inhibitory activity against WSN influenza virus with low cytotoxicity. Moreover, spiromastilactone D (6), a 5 -chloro-2 -methoxy substituted analogue, displayed the most potential to inhibit a panel of influenza A and B viruses including oseltamivir-and amantadine-resistant strains [17].

Antibacterial Activity
Since the isolation of penicillin, the antibacterial activity of metabolites of microfilamentous fungi has been the focus of investigations. Marine fungi are no exception in this sense. From 1998 to 2019, more than 270 compounds with antimicrobial properties were isolated from various marine-derived fungi [18].
Four new peptides were isolated from fungi Aspergillus allahabadii and A. ochraceopetaliformis (Jeju Island, Korea). Two compounds (13 and 14) from A. allahabadii were determined to be cyclopentapeptides, while those from A. ochraceopetaliformis were a structurally related cyclodepsihexapeptide (15) and its linear analogue (16). These new compounds exhibited moderate inhibition against the bacterial enzyme sortase A as well as a weak inhibition against isocitrate lyase [22].
Strong activity against Staphylococcus aureus and E. coli was reported for helvolinic acid (21) and helvolic acid (22) (Figure 3) from Aspergillus fumigatus MF071 (the Bohai Sea). A genomic data analysis revealed the putative biosynthetic gene clusters ftm for fumitremorgins, pso for pseurotins, fga for fumigaclavines, and hel for helvolinic acid. These putative biosynthetic gene clusters fundamentally underpinned the enzymatic and mechanistic function study for the biosynthesis of these compounds [24].
A new indoloditerpene (27) and fifteen known compounds were isolated from Aspergillus versicolor ZZ761 (Shengsi Island, the East China Sea). Compound 27 showed antimicrobial activities against Escherichia coli and Candida albicans [28].

Antifungal Activity
Antifungal activity is not rare for metabolites of marine sediment-derived fungi. Presumably, these compounds play a key role in interspecies relationships within fungal communities. Moreover, metabolites that inhibit the growth of aquatic and plant fungal pathogens are of particular importance from a practical point of view.
Tyrosol (58) from Penicillium chrysogenum DXY-1 (Taiwan Strait) was reported as a potential inhibitor of the quorum sensing (QS) systems to solve the looming crisis of bacterial resistance. The compound significantly decreased QS-regulated violacein production in Chromobacterium violaceum CV026 and QS-regulated pyocyanin production, elastase activity, and proteolytic activity in Pseudomonas aeruginosa PA01. Moreover, tyrosol inhibited biofilm formation in P. aeruginosa PA01 without having any effect on bacterial growth [43].
Polycyclic quinazoline alkaloid, thielaviazoline was obtained as a result of the microbial transformation of anthranilic acid by Thielavia sp. (Gomso Bay, South Korea, the Yellow Sea). Compound 63 displayed activity against MRSA and MDRSA. Moreover, compound 63 showed potent DPPH radical-scavenging activity [45].

Antifungal Activity
Antifungal activity is not rare for metabolites of marine sediment-derived fungi. Presumably, these compounds play a key role in interspecies relationships within fungal communities. Moreover, metabolites that inhibit the growth of aquatic and plant fungal pathogens are of particular importance from a practical point of view.

Plankton Toxicity
The toxicity of metabolites from marine fungi for phyto-and zooplankton organisms is also important for relationships of fungi in marine ecosystems. Nevertheless, the biological activity of compounds from marine sediment-derived fungi is reported as exceedingly rare.

Plankton Toxicity
The toxicity of metabolites from marine fungi for phyto-and zooplankton organisms is also important for relationships of fungi in marine ecosystems. Nevertheless, the biological activity of compounds from marine sediment-derived fungi is reported as exceedingly rare.

Cytotoxic Activity
According to the Global Burden of Disease Study project data, total cancers resulted in 23.6 million incident cases, 10 million deaths, and 250 million disability-adjusted life

Cytotoxic Activity
According to the Global Burden of Disease Study project data, total cancers resulted in 23.6 million incident cases, 10 million deaths, and 250 million disability-adjusted life years (DALYs) in 204 countries in 2019. Total cancers were the second-leading cause of death globally in 2019 and this trend has continued since 1990 [54].
As a result, the search for leader antitumor molecules among the metabolites of marine fungi is one of the stable modern trends in chemistry of natural compounds [55,56].
Two new epipolythiodiketopiperazines, named chetracins E (81) and F (82) (Figure 8) were isolated from the fungus Acrostalagmus luteoalbus HDN13-530 (Liaodong Bay, the Bohai Sea). All the compounds exhibited strong cytotoxicity against the five cancer cell lines. The computational docking indicated that compounds 81 and 82 could bind to the C-terminal of heat shock protein 90 (Hsp90), which was in line with the experimental observation of decreases in levels and active forms of Hsp90 client proteins [57]. New tetranorlabdane diterpenoid asperolide E (96) was isolated from Aspergillus wentii SD-310, a producer of antimicrobial isopimaranes 28-32. Asperolide E (96) displayed cytotoxic activities against the HeLa, MCF-7, and lung cancer NCI-H446 cell lines [65].
Two new drimane sesquiterpenes together with two known derivatives were isolated from Aspergillus flocculosus (Nha Trang Bay, the South China Sea). Compound 90 and its known nitrobenzoyl ester 91 exhibited cytotoxic activity toward human prostate cancer 22Rv1, human breast cancer MCF-7, and murine neuroblastoma Neuro-2a cells [60].
A new dimeric naphthopyrone, aurasperone H (93) (Figure 9), was isolated from Aspergillus niger 2HL-M-8 (northeast Brazilian coast, the Atlantic Ocean). Compound 93 exhibited moderate activity against the human lung adenocarcinoma A549 and the human leukemia HL-60 cell lines [62]. Another strain of Aspergillus niger from this location produced a new furoic acid derivative (94) that exhibited cytotoxicity against HCT-116 cell line [63].
Dicitrinone D (106) as a new polyketide was isolated from Penicillium citrinum (southeast coast of China). Dicitrinone D was safe for normal cells, but effectively inhibited the growth of human lung adenocarcinoma SPC-A1 cells [71].
A new diketopiperazine (107) was isolated from the Antarctic marine-derived fungus Penicillium crustosum HDN153086 (Prydz Bay, the Antarctic Ocean) and exhibited cytotoxicity against K562 cells [72]. A new alkaloid, 17-O-ethylnotoamide M (95), was isolated from a co-culture of marine sediment-derived fungi Aspergillus sulphureus KMM 4640 (East Sakhalin shelf, the Sea of Okhotsk) and Isaria felina KMM 4639 (the South China Sea, coast of Vietnam). Compound 95 inhibited the colony formation of human prostate cancer 22Rv1 cells [64].
Unique prostate cancer-toxic polyketides isariketides A (103) and B (104) were isolated from marine sediment-derived fungus Isaria felina (the South China Sea, coast of Vietnam) [69]. Compound 103 exhibited potent cytotoxicity against several lines of human prostate cancer cells, whereas 104 was inactive. Moreover, authors synthesized an acetate derivative of 103 that showed stronger cytotoxicity in comparison with 103.
New halogenated benzophenone derivatives pestalone C (120) and pestalone E (121), were obtained from Pestalotiopsis neglecta (Gagedo Island, the Yellow Sea). Isolated compounds suppressed pancreatic cancer cell line PANC-1 proliferation and induced apoptosis. An in silico study suggested that benzophenone derivatives could potentially inhibit MEK activity by binding to the allosteric pocket in MEK [77].
New halogenated benzophenone derivatives pestalone C (120) and pestalone E (121), were obtained from Pestalotiopsis neglecta (Gagedo Island, the Yellow Sea). Isolated compounds suppressed pancreatic cancer cell line PANC-1 proliferation and induced apoptosis. An in silico study suggested that benzophenone derivatives could potentially inhibit MEK activity by binding to the allosteric pocket in MEK [77].

Anti-Inflammatory Activity
Acute and chronic inflammation are the types of cellular response on foreign agent intervention, shock or injury, and hypersensitivity. Inflammation is a necessary response to maintain normal homeostasis in an organism that has been infected or injured. How- New anthraquinone derivatives, auxarthrols D-H, together with several known related compounds were obtained from fungus Sporendonema casei (Zhangzi Island, the Yellow Sea). Two of them, auxarthrols D (131) and F (132), showed moderate activities against a few human cancer cell lines. In addition, a weak activity against Mycobacterium phlei, Bacillus subtilis, Vibrio parahemolyticus and Pseudomonas aeruginosa was observed for known altersolanol B (133) [82].

Anti-Inflammatory Activity
Acute and chronic inflammation are the types of cellular response on foreign agent intervention, shock or injury, and hypersensitivity. Inflammation is a necessary response to maintain normal homeostasis in an organism that has been infected or injured. However, prolonged inflammation can cause serious cell and molecule damage which results in different diseases. Normally functioning cells maintain a balance between proinflammatory and anti-inflammatory mediators, and in the event of any action, this balance shifts. The production of proinflammatory mediators during inflammation is promoted by macrophages which include tumor necrosis factor (TNF-a), various interleukins, prostaglandins (PGs), nitric oxide (NO), and reactive oxygen species (ROS) [86]. An increase in the production of these pro-inflammatory mediators is observed in bacterial lipopolysaccharide (LPS)-treated macrophage or microglia cells which are used as inflammation cell models in the search for anti-inflammatory drug candidates. A recent review of anti-inflammatory substances from marine fungi covered the 130 compounds isolated between 2000 and 2018, but did not focus on the source of the fungi [87].
Three new compounds with novel open-ring butenolide skeletons were isolated from Aspergillus terreus Y10 (coastal area of Hainan, the South China Sea). One of them, asperteretal F (153) was found to dose-dependently inhibit tumor necrosis factor (TNF-α) generation [91].
culture. All four compounds exhibited moderate NO inhibitory activities without cytotoxic effects [90].
A number of new and known curvularin-type macrolides were isolated from fungus Penicillium sumatrense (the Indian Ocean). Only known dehydrocurvularin (175) showed significant inhibition activity towards LPS-induced nitric oxide production in RAW 264.7 macrophages [101].
A known polyketide metabolite citrinin H1 (176) was isolated from fungus Penicillium sp. SF-5629 (Ulgin, South Korea, the Sea of Japan). Citrinin H1 (176) inhibited NO and prostaglandin E2 production in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. Moreover, it was found to suppress cyclooxygenase-2 gene expression and the phosphorylation of inhibitor kappa B-α, to interrupt the nuclear translocation of nuclear factor kappa B, and to decrease the activation of p38 mitogen-activated protein kinase [102].

Radical Scavenging and Antioxidant Activities
Imbalance between the pro-oxidant and the antioxidant components of homeostatic systems, i.e., oxidative stress, results in different cellular pathological processes and diseases including diabetes, neurodegeneration, cardiovascular diseases, and others. Primary antioxidants scavenge radical species, converting them into more stable radicals or nonradical species. Secondary antioxidants quench singlet oxygen, decompose peroxides, chelate pro-oxidative metal ions, and inhibit oxidative enzymes. Moreover, four reactivitybased lines of defense have been identified: preventative antioxidants, radical scavengers, repair antioxidants, and those relying on adaptation mechanisms [103].

Influence on Protein Activity and Expression
Different proteins are molecular targets in the search for promising drug molecules. Researchers of anticancer candidates are focusing on proteins involved in cell cycle control and tumor growth as well as metastasis, apoptosis, and others. Bromodomaincontaining protein (BRD4) is the most extensively and thoroughly studied member of bromodomain and the extra-terminal domain family. BRD4 plays an important role in cell cycle control and can affect the processes of cell proliferation, apoptosis, and transcription.

Influence on Protein Activity and Expression
Different proteins are molecular targets in the search for promising drug molecules. Researchers of anticancer candidates are focusing on proteins involved in cell cycle control and tumor growth as well as metastasis, apoptosis, and others. Bromodomain-containing protein (BRD4) is the most extensively and thoroughly studied member of bromodomain and the extra-terminal domain family. BRD4 plays an important role in cell cycle control and can affect the processes of cell proliferation, apoptosis, and transcription. In addition to its role in tumors, BRD4 also plays an important role in inflammation, cardiovascular diseases, and viral infections [113]. Glycogen synthase kinase-3 (Gsk-3) is a conserved serine/threonine kinase that mainly participates in cell proliferation, development, stress, and inflammation in humans. Accumulating evidence has suggested that GSK 3 beta is correlated with tumorigenesis and progression. However, GSK 3 beta is controversial due to its bifacial roles of tumor suppression and activation. In addition, overexpression of GSK 3 beta is involved in tumor growth, and it contributes to cell sensitivity to chemotherapy [114]. Moreover, it was reported that Gsk-3 protein can be activated in SARS-CoV-2 viral infected cells which results in excessive oxidative stress via degradation of the nuclear factor erythroid 2-related factor (Nrf2) protein. Activated Gsk-3 also modulates CREB-DNA activity, phosphorylates NF-kappa B, and degrades beta-catenin, thus provoking systemic inflammation [115].
The prevalence of diabetes mellitus, especially type 2, has increased significantly by nearly 40% globally in the past 10 years (http://www.healthdata.org/results/gbd_ summaries/2019/diabetes-mellitus-level-3-cause, accessed on 25 December 2020). Various enzymes are considered as therapeutic targets for treating this socially significant disease. Alpha-glucosidase is a family of enzymes originating from the pancreas which play a role in the anabolism of 80-90% of carbohydrates consumed into glucose. Inhibition of these enzymes helps to prevent postprandial hyperglycemia and the formation of glycated end products [116]. Protein-tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling pathways and plays an important role in type 2 diabetes mellitus (T2DM), as its overexpression may induce insulin resistance [117].
The acetylcholinesterase enzyme (AChE) is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is the target of most of the clinically used drugs for the treatment of Alzheimer's disease [118].
Sterol O-acyltransferase (SOAT) is an endoplasmic reticulum resident, multitrans membrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. In addition to cholesterol, SOAT can use multiple sterols as substrates and activators. Because of its functional importance, SOAT is a potential drug target for Alzheimer's disease, atherosclerosis, and several types of cancers [119].
The heat shock proteins (Hsps), also named "housekeeping" proteins, constitute a large family of molecular chaperones. Their functions focus on protein folding and refolding and other mechanisms of cytoprotecting. Overexpression of Hsps enhances tolerance of cells to stress factors and increases its viability but it is good only for nonmalignant cells, for example in the case of neurodegenerative diseases. In cancer cells, Hsps overexpression results in its higher resistance to drug and radiation anticancer therapy. Thus, Hsps (especially Hsp70) are molecular targets for anticancer (Hsps inhibitors) [120] and cytoprotective (Hsps enhancers) [121] drugs.
New diorcinol J (237) and known diorcinol B (238) was obtained from the EtOAc extract of a co-culture of marine isolates of the fungi Aspergillus sulphureus KMM 4640 (the Sea of Okhotsk) and Isaria felina KMM 4639 (the South China Sea). The isolated compounds exhibited a weak hemolytic activity and cytotoxicity toward murine Ehrlich carcinoma cells. Moreover, known diorcinol B (238) was able to enhance expression of heat shock protein Hsp70 in Ehrlich ascites carcinoma cells [131].

Other Activities
Two new sesterterpenoids, terretonins H (239) and I (240), were isolated from Aspergillus ustus KMM 4664 (the Sea of Okhotsk). Compounds (Figure 21) inhibited the ability of spermatozoa to fertilize egg cells of the sea urchin Strongilocentrotus intermedius [132].

Other Activities
Two new sesterterpenoids, terretonins H (239) and I (240), were isolated from Aspergillus ustus KMM 4664 (the Sea of Okhotsk). Compounds (Figure 21) inhibited the ability of spermatozoa to fertilize egg cells of the sea urchin Strongilocentrotus intermedius [132].

Concluding Remarks
Marine sediment-derived fungi are exposed to both natural stress factors, to which adaptive mechanisms have already been developed during evolution, and modern challenges, namely the effect of high concentrations of xenobiotics entering sea water because of pollution and settling to the bottom. New phenalenone derivatives ent-peniciherqueinone (241) and 4-hydroxysclerodin (242), along with known compounds (243-244) of the herqueinone class, were isolated from Penicillium sp. (Gagudo, South Korea) [133]. 4-Hydroxysclerodin (242) exhibited moderate anti-angiogenetic and anti-inflammatory activities. Compound 243 moderately inhibited NO production in RAW 264.7 cells with an IC 50 value of 3.2 µM, while the rest of the isolated compounds were inactive (IC 50 > 20 µM). In the angiogenesis assay, 242 inhibited tube formation in HUVECs with an IC 50 of 20.9 µM, while ent-peniciherqueinone (241) and isoherqueinone (244) induced adipogenesis through PPAR binding and adiponectin secretion-promoting activity in hBM-MSCs and in a concentration-dependent manner, which was determined by adiponectin secretion-promoting effects with their IC 50 values of 57.5 µM and 39.7 µM, respectively.

Concluding Remarks
Marine sediment-derived fungi are exposed to both natural stress factors, to which adaptive mechanisms have already been developed during evolution, and modern challenges, namely the effect of high concentrations of xenobiotics entering sea water because of pollution and settling to the bottom.
Melanization of hyphae is one of the protection mechanisms against changes in osmotic pressure. Thus, adding tricyclazole, a specific inhibitor of the dihydroxynaphthalene (DHN) type of melanin, in Cirrenalia pygmea growth medium resulted in producing lightcolored hyphae which were highly susceptible to osmotic shock [136].
Changes in secondary metabolite production is a strategy for intracellular osmoregulation. Increasing salinity increased the activity of polyol enzymes such as polyol dehydrogenase and mannitol dehydrogenase and, finally, polyols content. Higher salinity also led to an increase in the amino acid pool size as well as glycogen and sterols. Moreover, higher salinity brought about a decrease in the extent of unsaturation of fatty acids. A hypo-osmotic shock resulted in a decrease in the polyol content [137].
Melanin and its related compounds are able to tolerate marine-derived fungi oxidative stress inducing UV radiation and xenobiotics. The isolation of melanin biosynthesis intermediates from marine-derived fungus and finding their antioxidant and cytoprotective activities confirms the role of them in cell protective machinery [138].
Dihydroxynaphthalene (DHN) melanin pathway is a basic melanin formation in fungi [139] and it is a special case of polyketide pathways which result in a big structural variety of polyketide metabolites [140].
In total, 246 compounds with various biological activities were reported from 2016 to November 2020 (Appendix A Table A1). In terms of chemical structures, most of them belong to polyketides (54%), and alkaloids (21%) and terpenoids (17%) combined are the second most common. The rarest bioactive compounds are peptides (4%) and meroterpenoids (4%) (Figure 22a). Changes in secondary metabolite production is a strategy for intracellular osmoregulation. Increasing salinity increased the activity of polyol enzymes such as polyol dehydrogenase and mannitol dehydrogenase and, finally, polyols content. Higher salinity also led to an increase in the amino acid pool size as well as glycogen and sterols. Moreover, higher salinity brought about a decrease in the extent of unsaturation of fatty acids. A hypo-osmotic shock resulted in a decrease in the polyol content [137].
Melanin and its related compounds are able to tolerate marine-derived fungi oxidative stress inducing UV radiation and xenobiotics. The isolation of melanin biosynthesis intermediates from marine-derived fungus and finding their antioxidant and cytoprotective activities confirms the role of them in cell protective machinery [138].
Dihydroxynaphthalene (DHN) melanin pathway is a basic melanin formation in fungi [139] and it is a special case of polyketide pathways which result in a big structural variety of polyketide metabolites [140].
In total, 246 compounds with various biological activities were reported from 2016 to November 2020 (Appendix A Table A1). In terms of chemical structures, most of them belong to polyketides (54%), and alkaloids (21%) and terpenoids (17%) combined are the second most common. The rarest bioactive compounds are peptides (4%) and meroterpenoids (4%) (Figure 22a). Antiviral activity against various subtypes of influenza virus and herpes simplex virus 1 has been reported for 12 compounds. For a number of reasons, an investigation of antiviral activity is one of the most difficult bioassays and this is a limiting factor for the discovery of new antiviral drug candidates. Nevertheless, the studying of secondary metabolites from marine sediment-derived fungi for their antiviral activity is promising. The COVID-19 pandemic showed humanity's vulnerability, but advances in this field, e.g., anti-HIV therapy, offer hope.
Antibacterial activity has been reported for 57 compounds from marine sedimentderived fungi. With the aim of helping to prioritize the research and development of new and effective antibiotic treatments, the WHO recently published a list of bacterial pathogens for which new antibiotics are urgently needed at a global level [141]. Priority I (critical) comprises carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and members of Enterobacteriaceae, that is, Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp. Representatives of the group Priority II (high) are vancomycin-resistant Enterococcus faecium and methicillinand/or vancomycin-resistant Staphylococcus aureus. Penicillin-non-susceptible Streptococcus pneumoniae, among others, belongs to Priority III (medium).
In this regard, such marine sediment-derived fungal metabolites as 2-(dimethoxymethyl)-1-hydroxyanthracene-9,10-dione (26), emerixanthone E (33), emerimicin IV (34), penicacid D (50), and tyrosol (58), which show significant activity against one or more these bacterial pathogens, may be of particular interest for further research.  Antiviral activity against various subtypes of influenza virus and herpes simplex virus 1 has been reported for 12 compounds. For a number of reasons, an investigation of antiviral activity is one of the most difficult bioassays and this is a limiting factor for the discovery of new antiviral drug candidates. Nevertheless, the studying of secondary metabolites from marine sediment-derived fungi for their antiviral activity is promising. The COVID-19 pandemic showed humanity's vulnerability, but advances in this field, e.g., anti-HIV therapy, offer hope.
Antibacterial activity has been reported for 57 compounds from marine sedimentderived fungi. With the aim of helping to prioritize the research and development of new and effective antibiotic treatments, the WHO recently published a list of bacterial pathogens for which new antibiotics are urgently needed at a global level [141]. Priority I (critical) comprises carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and members of Enterobacteriaceae, that is, Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp. Representatives of the group Priority II (high) are vancomycin-resistant Enterococcus faecium and methicillinand/or vancomycin-resistant Staphylococcus aureus. Penicillin-non-susceptible Streptococcus pneumoniae, among others, belongs to Priority III (medium).
Cytotoxic activity against various cancer line cells was reported for 62 compounds isolated from marine sediment-derived fungi.
Many natural and semi-synthetic compounds with various antitumor effects are published annually. At first glance, this does not seem to lead to the desired success in new low-molecular-weight drug development. At this time there is only one successful drug candidate for anticancer therapy among marine fungal metabolites. It is plinabulin, a synthetic derivative of phenylahistine (from algicolous Aspergillus ustus), that is under Phase II and III of clinical trials in complex therapy of various cancers [142]. From 2005 to 2015, cytotoxic activity was reported for 37% of isolated bioactive fungal metabolites (Introduction section) and from 2016 to 2020 it was reported only for 25% of the compounds (Figure 22b).
More than 70 secondary metabolites with various cytoprotective properties have been isolated from marine sediment-derived fungi from 2016 to now. Anti-inflammatory activity was described for 33 compounds. Radical scavenging and antioxidant activities were reported for 37 compounds and for 7 from them a neuroprotective effect was shown. Moreover, enhancing of Hsp70 expression was reported for one compound.
As was noted in the Introduction, only nine compounds with cytoprotective properties have been identified from 2005 to 2015. Of course, it should be borne in mind that the biological activity could have been studied and published later, but a change in the trend in the study of the biological effects of compounds is clearly visible.
It is obvious that further development of the field of marine fungal metabolites investigation will be determined by improvements of the existing isolation and identification techniques, as well as by the arrival of fundamentally new approaches. Moreover, at present, there is an increasing interest in studies of the fungal metabolome that give perspectives in complex estimation of biosynthetic abilities of fungal strains and the influence of ecological factors on fungal metabolomes. Using gene cluster technologies together with the metabolome approach will allow controlling of the fungal biosynthetic pathways to obtain metabolites with the expected biological properties.  Acknowledgments: The authors dedicate this review to the memory of Shamil Afiyatullov, who made a great contribution to the study of marine fungal metabolites of the Pacific region. The authors thank Sophia Kolesnikova (G.B. Elyakov Pacific Institute of Bioorganic Chemistry) for the valuable comments.