Diversity of source, chemistry, and bioactivities of secondary metabolites from algae-associated and sponge-associated fungi

Marine-derived fungi have been evident sources of new secondary metabolites with an incredible diversity of structural and bioactivity. The accretion of research into discovering new secondary metabolites from marine-derived fungi has continued upward over the last few years. Marine-derived fungi have been found and isolated from various marine habitats, including sponges and algae. This review report displays the structures of new compounds isolated from algae-derived and sponge-derived fungi and their activities, covering the literature from 2017 to 2021. A total of 339 new compound structures were reported in this study, of which 169 compounds were distributed from algae-derived fungi and 170 were isolated from sponge-derived fungi. The compounds distributed were classified as alkaloids, aromatics, lactones, peptides, polyketides, pyrones, steroids, and terpenes isolated from Trichoderma sp., Aspergillus sp., Penicillium sp., Alternaria sp., Talaromyces sp., Acremonium sp., and Pestalotiopsis sp. Based on activity, these compounds have various activities such as antibacterial, cytotoxic, antioxidant, antifungal, anti-inflammatory, and butyrylcholinesterase inhibition. Several compounds showed stronger activity than the control. In the end, a review of this report can provide information on the great potential of discovering and developing new compounds to be used as led compounds derived from marine fungi.


INTRODUCTION
Marine microorganisms have been reported as one of the sources of compounds developed and used as drug agents, considering 75% of living organisms come from the marine environment (Saeed et al., 2021;Stincone and Brandelli, 2020).Previous reports supported the successful development of drugs from the marine environment has a success rate four times higher than other naturally derived compounds (Sigwart et al., 2021).Marine endophytic fungi are microorganisms that have produced potential compounds for drugs (El-Bondkly et al., 2021).Endophytic fungi have been discovered and isolated from various marine habitats, including sponges, mangroves, algae, and seagrasses, that have antifungal, anti-inflammatory, anticancer, antibacterial, antiviral, antiparasitic, immunosuppressive, and antioxidant activities (El-Bondkly et al., 2021).
Algal and sponges have much diversity and are important ecosystems in marine environments and even the world (Amelia et al., 2022;McCoy and Kamenos, 2015).Algae and sponges have benefited marine biotas such as fish and shellfish (Amelia et al., 2022;McCoy and Kamenos, 2015).In addition, algae and coral have long been used by humans in various fields, including the fishing industry, health, coastal protection, and tourism (Berdalet et al., 2016;Eastwood et al., 2017;Hoegh-Guldberg et al., 2007).For microorganisms, algae and sponges become ideal symbiosis places (Van de Water et al., 2018).Several studies have revealed communication between fungi and their symbiotic place, including algae and sponges (Zuluaga-Montero et al., 2010).However, the detailed symbiotic interactions between them are still not widely studied (Van de Water et al., 2018).The fungi isolated from algae or sponges are quite varied species-wise and produce quite various activities of secondary metabolites (Chen et al., 2022;Gao and Zhang, 2022).
A wide variety of algae-associated fungi and spongeassociated fungi has been isolated, producing new and known compounds (Chen et al., 2022;Gao and Zhang, 2022).The compounds have been reported to have biological activity, and some of them have become lead compounds to be developed and used in clinical applications (Saeed et al., 2021).In this review, we presented the diversity of sources, chemistries, and bioactivities of new compounds isolated from algae-associated and sponge-associated fungi gathered from the literature from 2017 to 2021.It covers 339 secondary metabolites focusing on the classification of compounds as fungi-producing, host-associated, and bioactive, and a comparison between algae-associated and sponge-associated fungi was made.Zhang et al. (2020) reviewed the diversity of bioactivity and structure of 571 metabolites from sponge-associated fungi and gathered the literature from 2010 to 2018.In another review in 2022, Gao and Zhang (2022) reported a total of 196 new metabolites isolated from algae-associated fungi covering from 2016 to 2021, including the chemical diversity and biological activities.
Although the fungi are greatly disparate in terrestrial and marine environments, marine-derived fungi dominate fungal diversity.Environmental diversity, such as alterations in temperature, pressure, light, and mineral composition, such as salt levels, may affect the diversity of fungi inhabiting marine environments.Several studies have shown that the diversity of fungi varies according to their host genus.In this review, the variegated species to their algae-host genus were obtained from 21 algae.As depicted in Figure 2A, 18%, 15%, and 8% of these fungi are derived from Rhodomela sp., Gracilaria sp., and Sargassum sp., respectively, and others were isolated from Laurencia sp., Chondria sp., Grateloupia sp., Chondrus sp., Pterocladiella sp., Ulva lactuca, Laminaria sp., Asparagopsis sp., Lomentaria sp., Coelarthrum sp., Mastophora rosea, Padina sp., Undaria pinnatifida, Ceramium japonicum, Codium fragile, Fucus vesiculosus, Enteromorpha prolifera, and Symphyocladia latiuscula.Three of these algae are green algae, namely, U. lactuca, C. fragile, and E. prolifera, whereas the others are red and brown algae, and the red algae dominate as a source of fungi.The red and brown algae possess a high diversity of fungi that are the most important hosts of fungi from the marine.In contrast, the diversity of fungi from green algal is lower, which may be because of the comparatively short life cycle of green algae.
In addition to their classification as chemical, fungiproducing, and host-associated, these new secondary metabolites from algae-associated fungi possess exceptional biological activities.A total of 90 compounds were reported to have biological activities in which anti-marine-phytoplankton, antibacterial, and cytotoxicity activities are dominating capabilities in these new secondary metabolites with 21%, 11%, and 7%, respectively.Other activities include antimicroalgal, antioxidant, antifungal, anti-inflammatory, insecticidal, angiotensin-converting enzyme (ACE) inhibitory, acetylcholinesterase (AChE) inhibitory, and antiangiogenic (Fig. 2B).

Terpenes
Terpenes are a class of compounds that are widely produced by fungi and have diverse biological activities.Terpenes are reported to have antibacterial, antifungal, and antiviral activities.Some terpenes show a broad spectrum of antibacterial activities.In this report, terpenes are the most widely isolated group of compounds from fungi symbiotic with algae, with as many as 101 compounds.A total of 78 compounds were reported isolated from the fungus Trichoderma spp., and others were isolated from Alternaria alternata, Aspergillus sydowii, Chondrostereum sp., Nemania bipapillata, and Penicillium chrysogenum.Based on biological activity, they are reported to have antibacterial, antifungal, antimicroalgal, anti-inflammation, antioxidant activities, and cytotoxicity and inhibition of marine phytoplankton.In this part, detailed descriptions of classified terpenes are provided below.

Alkaloids
Alkaloids are a substantial and structurally diverse group of natural and liable for beneficial biological activities.Alkaloids have enthusiastically contributed to the development of drugs in various aspects, including synthesis, structural alteration, and substructures, which remain the focus of much research.The alkaloids were reported as compounds isolated from fungi in marine habitats.The unique complexity of structure causes the biological activity of alkaloids from marine fungi to be quite varied and strong.In this report, 18 alkaloids have been reported from algaeassociated fungi along with their biological activities.Penicillium sp.strain KMM 4672 isolated from Padina sp.produced four diketopiperazine alkaloids, namely citriperazine A-D (102-105), which have cytotoxic activity in human prostate cell lines (Yurchenko et al., 2020).Li et al. (2021) reported that three diketopiperazines alkaloids were isolated from Aspergillus creber EN-602, obtained from the red algae R. confervoides, namely, 3-hydroxyprotuboxepin K (106), 3,15-dehydroprotuboxepin K (107), and versiamide A (108) (Fig. 6).Compound 106 had ACE inhibitory activity (IC 50 = 22.4 μM and 107 and 108 had antimicrobial activity in the various aquatic bacteria (MIC = from 8 to 64 μg/ml).

Sponge-associated fungi
In recent years, an augmentative number of studies highlighted that many active secondary metabolites from sponges are of microorganism origin due to similar chemical structures found in terrestrial microorganisms.Of many marine organisms, sponges are considered the most prolific source of therapeutic compounds as these animals harbor many secondary metabolites, many of which are worthwhile for human health.Spongeassociated fungi are a group of microorganisms found to produce secondary metabolites.
The new secondary metabolites produced by spongeassociated fungi are a diverse array of structures observed.The majority of the new secondary metabolites are lactones (19%), polyketides (18%), alkaloids (16%), and aromatics (16%) (Fig. 12A).In addition to the diverse structures, the new secondary metabolites derived from sponge-associated fungi exhibit diverse and pronounced biological activities.Antimicrobial activity and cytotoxicity are the most prominent activities, as indicated by 12 and 11% of the new secondary metabolites.Other activities include IL-6 immune-suppressive, antifungal, anti-inflammatory, NF-α immune-suppressive, antioxidant, alpha-glucosidase inhibitors, anti-BChE, anti-Aβ fibrillization, anti-Mycobacterium tuberculosis, and antiviral effects (Fig. 12B).

Comparative of algae-associated and sponge-associated fungi
Algae-and sponge-associated fungi are the two groups of endophytic fungi found to produce new secondary metabolites.As shown in Figure 21, Trichoderma is described as the greatly predominant producers of new secondary metabolites from algaeassociated fungi, while Aspergillus sp. is predominant in spongeassociated fungi.Penicillium sp. and T. stipitatus sp. are fungi that constantly produce new secondary metabolites.The remaining new secondary metabolites were produced by 28 fungi.Although fungi are highly disparate in terrestrial and marine habitats, marinederived fungi possess more diversity.As noted before, drivers of nutrition, heat, air pressure, and light may affect the diversity of marine-derived fungi.Moreover, several reviews have indicated that the diversity of marine-derived fungi varied according to their host genus.In this review, the fungal producers of new secondary metabolites were explored from 21 algae and 23 sponges.
In this review, new secondary metabolites produced by algae-and sponge-derived fungi possessed a high structural diversity.A total of 339 new secondary metabolites were isolated from algae-derived fungi and sponge-derived fungi, which are categorized into terpenes, alkaloids, aromatics, polyketides, lactones, peptides, and steroids.Terpenoids produced the most algae-associated fungi and the least sponge-associated fungi, while lactones, polyketides, alkaloids, and aromatics were produced equally by sponge-associated fungi, as represented in Figure 22.
In addition to the high structural diversity, the new secondary metabolites derived from algae-associated fungi and sponge-associated fungi show diverse and apparent biological activities.As represented in Figure 23, 173 (34%) new secondary   metabolites isolated from algae-associated fungi and spongeassociated fungi are found to possess considerable biological activities, of which 73 new secondary metabolites exhibit potent antibacterial and cytotoxicity activity.Moreover, some of the new secondary metabolites are shown to have one or more varieties of biological activities and are shown to have moderate to potent bioactivities.These strong bioactivities create some of the new secondary metabolite preferable candidates for developing new drugs, agrochemicals, and lead compounds in the future.

CONCLUSION
Marine algae and sponges are exceptional fungal sources for producing new secondary metabolites.From 2017 to 2021, natural product research into algae-derived fungi and spongederived fungi led to 339 new secondary metabolites.These new secondary metabolites were observed to have significantly varied in structure and various bioactivities.These new secondary metabolites have great potential in treating diseases.However, the bioactivities of these new secondary metabolites were exclusively in vitro tested; thus, there is more interest in in vivo studies for the molecular mechanism.Furthermore, there is great potential in discovering and developing new compounds to be used as led compounds derived from algae-associated and sponge-associated fungi.

PUBLISHER'S NOTE
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Figure 1 .
Figure 1.Distributions of new compounds produced algae-associated and their activities.Distribution of the secondary metabolites corresponding to the chemical structure (A) and fungi-producing (B).

Figure 2 .
Figure 2. Distributions of new compounds produced algae-associated and their activities.Distribution of the secondary metabolites corresponding to the biological activity (A) and algae-associated (B).

Figure 11 .
Figure 11.Distributions of sponge-associated new compounds.Distribution of the fungi-producing (A) and sponge-associated (B) secondary metabolites.

Figure 12 .
Figure 12.Distributions of sponge-associated new compounds.Distribution of the secondary metabolites corresponding to the chemical structure (A) and biological activity (B).

Figure 21 .
Figure 21.Comparison of fungal producers of new secondary metabolites.

Figure 22 .
Figure 22.Comparison of secondary metabolites corresponding to the chemical structure.

Figure 23 .
Figure 23.Comparison of biological activities isolated from algae-associated fungi and sponge-associated fungi.