Biological and Chemical Diversity of Marine Sponge-Derived Microorganisms over the Last Two Decades from 1998 to 2017

Marine sponges are well known as rich sources of biologically natural products. Growing evidence indicates that sponges harbor a wealth of microorganisms in their bodies, which are likely to be the true producers of bioactive secondary metabolites. In order to promote the study of natural product chemistry and explore the relationship between microorganisms and their sponge hosts, in this review, we give a comprehensive overview of the structures, sources, and activities of the 774 new marine natural products from sponge-derived microorganisms described over the last two decades from 1998 to 2017.


Introduction
The term "symbiosis" was first defined by the German mycologist Heinrich Anton de Bary in 1879 as "the living together of unlike organisms" [1]. Symbiosis is an intimate and long-term biological interaction between two different biological organisms, whether reciprocal, symbiotic, or parasitic. It is abundant and widespread in the sea for symbioses between microorganisms and marine organisms. Most marine animals and plants such as sponges, corals, sea squirts, worms, and algae host contain diverse and abundant symbiotic microorganisms. Among them, sponge is the most primitive type of metazoan, which has been used as an important source of marine active compounds. There are many types of sponges (between 10,000 and 15,000 species), accounting for 6.7% of all marine animal species. At present, detected sponges can be divided into four classes: Calcarea (about 400 species), Hexactinellida (about 600 species), Demospongiae (about 4000 species), and Homoscleromorpha (about 15 species). Sponges are multicellular filter feeders, in which a layer of flagellum cells arranged in the body cavity of the sponge provides nutrients and oxygen to the spongy body through the generated water flow. Its unique pore structure makes it an excellent host for many marine microorganisms, which account for a large amount of sponge biomass. Some studies have shown that the true source of secondary metabolites in sponges may be their symbiotic microbes. Therefore, a comprehensive

Order Biemnida
Family Rhabderemiidae A study on the fungus Aspergillus similanensis KUFA 0013 isolated from the sponge Rhabderemia sp. (Thailand) resulted in two new isocoumarin derivatives (128-129), a new chevalone derivative

Family Clionaidae
A new compound, namely butylrolactone-VI (147) (Figure 9), was metabolized by the fungus Aspergillus sp. (2P-22) associated with the marine sponge Cliona chilensis (collected in the Pacific Sea, Chile), and its antibacterial and antitumor activities were determined [51]. A unique O-glycosylated disubstituted Microluside A (148) (Figure 9) was isolated from Micrococcus sp. EG45 associated with the Red Sea sponge Spheciospongia vagabunda, which exhibited antibacterial potential against Enterococcus faecalis JH212 and Staphylococcus aureus NCTC 8325 with MIC values of 10 and 13 μM, respectively [52]. From the actinomycete Actinokineospora sp. EG49 cultivated in Red Sea sponge

Family Thorectidae
Six new polyketides, engyodontochone A-F (184-189) (Figure 12), were purified in fungus Engyodontium album strain LF069 originally separated from the sponge tissue of Cacospinga scalaris sampled at the Limski Fjord, Croatia. Compounds 186-189 represented the first example of a 23, a 28 seco-beticolin carbon skeleton, and compounds 184-185 exhibited inhibitory activity that was 10-fold stronger than chloramphenicol against methicillin-resistant Staphylococcus aureus [69]. The strain Pseudoalteromonas maricaloris KMM 636 T derived from the Australian sponge Fascaplysinopsis reticulata collected at the Great Barrier Reef was found to produce an inseparable mixture of two brominated yellow main pigments, bromoalterochromide A and A (190) (Figure 12) in a ratio of 3:1. They showed cytotoxic effects on developing eggs of the sea urchin Strongylocentrotus intermedius (MIC, 40 µg/mL) [70].  The cultures of Aspergillus niger separated from a Caribbean sponge, Hyrtios proteus, collected in the Dry Tortugas National Park, Florida, resulted in the isolation of a tetrahydrofuran-type derivative asperic acid (191) (Figure 13) [71]. The fungus Emericellopsis minima derived from the marine sponge Hyrtios erecta (Thailand) afforded a new bridged cyclic sesquiterpene (192) (Figure  13) [72]. A new alkaloid with an unprecedented carbon skeleton, penicillivinacine (193) (Figure 13), was produced by the fungus Penicillium vinaceum, which is associated with the marine sponge Hyrtios erectus (collected from Yanbu, Saudi Arabia). Compound 193 exhibited higher antimigratory activity than the positive control with an IC50 value of 18.4 μM against the human breast cancer cell line MDA-MB-231 [73]. Examination of the fungus Trichoderma harzinum HMS-15-3 derived from the The cultures of Aspergillus niger separated from a Caribbean sponge, Hyrtios proteus, collected in the Dry Tortugas National Park, Florida, resulted in the isolation of a tetrahydrofuran-type derivative asperic acid (191) (Figure 13) [71]. The fungus Emericellopsis minima derived from the marine sponge Hyrtios erecta (Thailand) afforded a new bridged cyclic sesquiterpene (192) (Figure 13) [72]. A new alkaloid with an unprecedented carbon skeleton, penicillivinacine (193) (Figure 13), was produced by the fungus Penicillium vinaceum, which is associated with the marine sponge Hyrtios erectus (collected from Yanbu, Saudi Arabia). Compound 193 exhibited higher antimigratory activity than the positive control with an IC 50 value of 18.4 µM against the human breast cancer cell line MDA-MB-231 [73]. Examination of the fungus Trichoderma harzinum HMS-15-3 derived from the sponge Petrospongia nigra collected from South China Sea provided four pairs of new linear C 13 lipid enantiomers with polyene and O-dinol structure, namely harzianumols A-H (194)(195)(196)(197)(198)(199)(200)(201) (Figure 13). Their antihyperlipidemic effects in HepG2 cells were evaluated [74]. Hainan Sanya, China. Two new pyripyropenes (209-210) ( Figure 13) were isolated from the other fungus Fusarium lateritium 2016F18-1, which is associated with the same sponge [75,76].
Chemical examination of a marine fungus Alternaria sp. JJY-32, isolated from a sponge
previously isolated from the sponge of Niphates sp. collected from Southern China Sea. Punctaporonin K (343) exhibited potent effects to reduce the triglycerides and total cholesterol in the intracellular levels. Compounds 340-345 showed weak cytotoxic activity against a panel of tumor cell lines with IC50 values more than 10 μM and showed weak inhibitory effects against the bacterial strains with the MIC values more than 125 μM. Compounds 346-358 did not do well in their bioassays [112][113][114].

Family Myxillidae
A new equisetin-like tetramic acid derivative, beauversetin (440) (Figure 25), was isolated from the sponge-derived fungus Beauveria bassiana; in turn, this was isolated from the sponge Myxilla incrustans, which was collected from the island of Helgoland. Compound 440 exihibited moderate anti-tumor activity against a six-cell line panel for a monolayer assay (IC50, 3.09 μg/mL) [145].

Family Myxillidae
A new equisetin-like tetramic acid derivative, beauversetin (440) (Figure 25), was isolated from the sponge-derived fungus Beauveria bassiana; in turn, this was isolated from the sponge Myxilla incrustans, which was collected from the island of Helgoland. Compound 440 exihibited moderate anti-tumor activity against a six-cell line panel for a monolayer assay (IC 50 , 3.09 µg/mL) [145].

Order Tethyida
Family Tethyidae A fungal strain, Scopulariopsis brevicaulis, was obtained from the marine sponge Tethya aurantium (collected in Croatia), and it was found to produce two novel cyclodepsipeptides, scopularides A-B (556-557) (Figure 34). Both compounds exhibited significant activity against
Compound 563 selectively inhibited Vibrio species, and compound 564 showed a broad spectrum of antibacterial activity with MIC values between 0.01 and 0.1 μg/mL [187].

Family Ancorinidae
A new polyketide, deoxynortrichoharzin (567) (Figure 35), was produced by the marine-derived fungus Paecilomyces cf. javanica, which is a symbiont on the sponge Jaspis cf. coriacea

Family Ancorinidae
A new polyketide, deoxynortrichoharzin (567) (Figure 35), was produced by the marine-derived fungus Paecilomyces cf. javanica, which is a symbiont on the sponge Jaspis cf. coriacea (collected in the Fiji Islands). Compound 567 did not show any activity in solid-tumor cells in culture [190]. A new bile acid derivative (568) (Figure 35) was metabolized by a marine sponge-associated bacterium Psychrobacter sp. associated with the marine sponge Stelletta sp., which was collected off the coast of Geoje Island, Korea. Compound 568 exhibited moderate suppressive effects on both NO and interleukin-6 (IL-6) production at a concentration of 87.3 µg/mL [191]. New sesquiterpenoids (569-572) ( Figure 35) were isolated from the fungal strain Acremonium sp., which was isolated from a marine sponge Stelletta sp. (collected in Korea). Compound 569 exhibited weak anti-inflammatory activity in RAW 264.7 murine macrophage cells [192]. A bacterial strain J05B1-11, isolated from the marine sponge Stelletta sp. (Korea), yielded a new natural product: Sym-Tetra (573) (Figure 35). Compound 573 was non-cytotoxic according to this study [193]. Four new hexylitaconic acid derivatives (574-577) ( Figure 35) were isolated from a sponge-derived fungus Penicillium sp., which was isolated from a sponge Stelletta sp. collected in Jeju island, Korea [194]. The investigation of the fungus Aspergillus sydowii from the sponge Stelletta sp. yielded two new metabolites, diorcinolic acid (578) and β-D-glucopyranosyl aspergillusene A (579) (Figure 35). Compounds 578-579 showed mild cytotoxicity against several human cancer cells with IC 50 values ranging from 50 to 70 µM [195].

Family Theonellidae
Chemical examination of a marine-derived Escherichia coli from the sponge Discodermia calyx (collected in Japan) afforded a novel pyridinium with three indole moieties: tricepyridinium 610 ( Figure 37). 610 showed antimicrobial activity against B. cereus, S. aureus, and C. albicans (with MIC values of 0.78, 1.56, and 12.5 µg/mL, respectively) and cytotoxicity to P388 cells with an IC 50 value of 0.53 µg/mL [204]. Study on the metabolites of the sponge-derived Streptomyces sp. GIC10-1 derived from the sponge Theonella sp.  [206,207]. A new compound named hortein (619) (Figure 38) was isolated from the fungus Hortaea werneckii isolated from the Mediterranean sponge Aplysina aerophoba. When tested for antibiotic or insecticidal activity, the bioassays were disappointing [208]. The strain of the fungus Cladosporium herbarum, isolated from the sponges Aplysina aerophoba collected in the Mediterranean Sea, yielded two new R-pyrones, herbarin A-B (620-621) ( Figure 38). Compounds 620 and 621 showed activity against Artemia salina but exhibited no significant antibiotic activity [79]. A new glutarimide (622) (Figure 38) was isolated from a marine-derived Streptomyces anulatus S71 isolated from a marine sponge Aplysina aerophoba (South China Sea) [209].

Geographical Distribution of Sponge-Derived Microorganisms
As what we described above, temperate and tropical sea areas have become the main regions with sponge-derived microorganisms related to natural product chemistry. Figure 46 presented a visible-direct sketch map for geographical distribution of sponge-derived microorganisms. The studied species of microbial communities associated with sponges has so far mostly been focused on the Pacific coasts, including the South China Sea, Sea of Japan, Gulf of Thailand, Korean Peninsula, Indonesian Islands, Eastern China Sea, and the Great Barrier Reef, Australia. Of these, the South China Sea and the Sea of Japan are the most active hotspots, and the followings are the Mediterranean Sea, the West Atlantic Ocean, including the Gulf of Mexico and the Caribbean Island, the North Sea, the Black Sea, and then the Red Sea.

Geographical Distribution of Sponge-Derived Microorganisms
As what we described above, temperate and tropical sea areas have become the main regions with sponge-derived microorganisms related to natural product chemistry. Figure 46 presented a visible-direct sketch map for geographical distribution of sponge-derived microorganisms. The studied species of microbial communities associated with sponges has so far mostly been focused on the Pacific coasts, including the South China Sea, Sea of Japan, Gulf of Thailand, Korean Peninsula, Indonesian Islands, Eastern China Sea, and the Great Barrier Reef, Australia. Of these, the South China Sea and the Sea of Japan are the most active hotspots, and the followings are the Mediterranean Sea, the West Atlantic Ocean, including the Gulf of Mexico and the Caribbean Island, the North Sea, the Black Sea, and then the Red Sea.

Biodiversity of Microbial-Associated Sponge Hosts
The statistical data shows that all the sponge hosts associated with microbes were distributed in the classes of Calcarea, Demospongiae, and unidentified sponges. The class Demospongiae sponges accounts for absolute majority at 77%, the class Calcarea and others sponges account for 1% and 22%, respectively. In the class Demospongiae, the order Haplosclerida provides the most sponge species accounting for 26.75% of the totality, followed by the orders Suberitida, Axinellida, Dictyoceratida, Tetractinellida, and Poecilosclerida etc. (see Figure 47).

Biodiversity of Microbial-Associated Sponge Hosts
The statistical data shows that all the sponge hosts associated with microbes were distributed in the classes of Calcarea, Demospongiae, and unidentified sponges. The class Demospongiae sponges accounts for absolute majority at 77%, the class Calcarea and others sponges account for 1% and 22%, respectively. In the class Demospongiae, the order Haplosclerida provides the most sponge species accounting for 26.75% of the totality, followed by the orders Suberitida, Axinellida, Dictyoceratida, Tetractinellida, and Poecilosclerida etc. (see Figure 47).

Biodiversity of Sponge-Derived Microorganisms
In the process of long-term co-evolution, there may be some sponge-derived microbes with wonderful symbiotic relationships in the sponge ecosystem, which cover fungi, bacteria, actinomycetes, cyanobacteria, and archaea. With no doubt, fungi, bacteria and actinomycetes are the main producers of prolific natural products with therapeutic effects among the sponge-derived microbes (see Figure 48), and the microbes appear to be distributed randomly in the investigated host sponges. Fungi are an important component of sponge-derived microbes-up to 73%-and more than 55 genera strains have been cultured. The fungi studied mainly belonged to the genera Aspergillus and Penicillium, followed by Trichoderma, Acremonium, Arthrinium, and Talaromyces. The genera Aspergillus and Penicillium obtained from many different sponge species take a percentage of 25% of the total microbes reported, the majority of which displayed wonderful chemistry diversity. Actinomycetes and bacteria account for 16% and 11% of sponge-derived microbes, respectively, which offered many novel and unique compounds. The actinomycetes studied were mainly derived from the genera Streptomyces, and the bacteria were mainly derived from the genera Pseudomonas, Pseudoalteromonas, and Bacillus (see Figure 48). In the process of long-term co-evolution, there may be some sponge-derived microbes with wonderful symbiotic relationships in the sponge ecosystem, which cover fungi, bacteria, actinomycetes, cyanobacteria, and archaea. With no doubt, fungi, bacteria and actinomycetes are the main producers of prolific natural products with therapeutic effects among the sponge-derived microbes (see Figure 48), and the microbes appear to be distributed randomly in the investigated host sponges. Fungi are an important component of sponge-derived microbes-up to 73%-and more than 55 genera strains have been cultured. The fungi studied mainly belonged to the genera Aspergillus and Penicillium, followed by Trichoderma, Acremonium, Arthrinium, and Talaromyces. The genera Aspergillus and Penicillium obtained from many different sponge species take a percentage of 25% of the total microbes reported, the majority of which displayed wonderful chemistry diversity. Actinomycetes and bacteria account for 16% and 11% of sponge-derived microbes, respectively, which offered many novel and unique compounds. The actinomycetes studied were mainly derived from the genera Streptomyces, and the bacteria were mainly derived from the genera Pseudomonas, Pseudoalteromonas, and Bacillus (see Figure 48).

Chemical Diversity and Bioactive Diversity of Sponge-Derived Microorganisms
A total of 774 new compounds, which were assorted into nine types including terpenes, alkaloids, peptides, aromatics, meroterpenoids, macrolides, polyketides, steroids, and miscellaneous ( Figure 49), were reported in the 253 studies in the literature. Among them, the number of the aromatics and the alkaloids takes a percentage of 45%, which suggests that we should pay more attention to the study of these two kinds of compounds.

Chemical Diversity and Bioactive Diversity of Sponge-Derived Microorganisms
A total of 774 new compounds, which were assorted into nine types including terpenes, alkaloids, peptides, aromatics, meroterpenoids, macrolides, polyketides, steroids, and miscellaneous ( Figure 49), were reported in the 253 studies in the literature. Among them, the number of the aromatics and the alkaloids takes a percentage of 45%, which suggests that we should pay more attention to the study of these two kinds of compounds.
Natural products isolated from sponge-derived microorganisms have interesting pharmaceutical activities such as cytotoxicity, antioxidant, antifungal, antiviral, and antibacterial activities. Some novel compounds showed significant cytotoxic activities in the nM levels, such as two new indolocarbazole alkaloids [13] and linear pentadecapeptides efrapeptin Eα [29]. Some new compounds exhibited activities stronger than the positive controls. Engyodontochone A-B exhibited inhibitory activity that was 10-fold stronger than chloramphenicol against MRSA [69]. A new pyronepolyene C-glucoside exhibited significant inhibitory effects in the cytopathic effect inhibition assay with an IC 50 value of 91.5 µM (ribavirin as a positive control, IC 50 114.8 µM) [86]. Truncateol M showed significant inhibitory effects with an IC 50 value of 8.8 µM against H1N1 virus (oseltamivir as a positive control, IC 50 46.5 µM) [101]. Dankastatin C (687) showed potent cell growth inhibitory activity against the murine P388 cell line with an ED 50 value of 57 ng/mL (5-fluorouracil as a positive control, ED 50 , 78 ng/mL) [236]. As we reported, the diketopiperazine alkaloid amauromine shows affinity for cannabinoid CB1 receptors, which may have potential as a lead structure for drug development [63]. Another noteworthy fact is the discovery of two new compounds-emindole SB betamannoside and 27-O-methylasporyzin C-that may serve as lead structures for the development of GPR18-and CB receptor-blocking drugs [88]. Compounds isolated from the sponge-derived microorganisms have various activities, and in addition to the above, they also exhibit anti-cholesterol activity [112], antiplasmodial activity [81,134], neuroprotective effects [26,178], and so on. The reported bioactivities are limited by many factors and they are not comprehensive, which suggests that these natural compounds should be screened on a wider variety of bioassays in order to unveil their full potential. Natural products isolated from sponge-derived microorganisms have interesting pharmaceutical activities such as cytotoxicity, antioxidant, antifungal, antiviral, and antibacterial activities. Some novel compounds showed significant cytotoxic activities in the nM levels, such as two new indolocarbazole alkaloids [13] and linear pentadecapeptides efrapeptin Eα [29]. Some new compounds exhibited activities stronger than the positive controls. Engyodontochone A-B exhibited inhibitory activity that was 10-fold stronger than chloramphenicol against MRSA [69]. A new pyronepolyene C-glucoside exhibited significant inhibitory effects in the cytopathic effect inhibition assay with an IC50 value of 91.5 μM (ribavirin as a positive control, IC50 114.8 μM) [86]. Truncateol M showed significant inhibitory effects with an IC50 value of 8.8 μM against H1N1 virus (oseltamivir as a positive control, IC50 46.5 μM) [101]. Dankastatin C (687) showed potent cell growth inhibitory activity against the murine P388 cell line with an ED50 value of 57 ng/mL (5-fluorouracil as a positive control, ED50, 78 ng/mL) [236]. As we reported, the diketopiperazine alkaloid amauromine shows affinity for cannabinoid CB1 receptors, which may have potential as a lead structure for drug development [63]. Another noteworthy fact is the discovery of two new compounds-emindole SB betamannoside and 27-O-methylasporyzin C-that may serve as lead structures for the development of GPR18-and CB receptor-blocking drugs [88]. Compounds isolated from the sponge-derived microorganisms have various activities, and in addition to the above, they also exhibit anti-cholesterol activity [112], antiplasmodial activity [81,134], neuroprotective effects [26,178], and so on. The reported bioactivities are limited by many factors and they are not comprehensive, which suggests that these natural compounds should be screened on a wider variety of bioassays in order to unveil their full potential.

Conclusion
A total of 774 new compounds from sponge-derived microorganisms, covering the last two decades from 1998 to 2017, were reviewed. These new compounds presented abundant chemical

Conclusions
A total of 774 new compounds from sponge-derived microorganisms, covering the last two decades from 1998 to 2017, were reviewed. These new compounds presented abundant chemical diversity except for the well-known types such as terpenes, alkaloids, peptides, aromatics, meroterpenoids, macrolides, polyketides, steroids, and so on.
The total amount of new compounds from sponge-derived microorganisms has increased rapidly and has not yet reached a climax, especially in the last five years (see Figure 50). Among the compounds of the sponge-derived microorganisms obtained, more than 42% of the compounds have detected activities; however, most of them only carried out preliminary active in vitro test experiments.
We should make more efforts to study the pharmacodynamic relationships and pharmacological effects of promising compounds, and conduct clinical trials to complete the drug-like evaluation of the compound. The study on the chemical constituents of sponges and their co-existing microorganisms will promote the study of the relationship between sponges and their co-existing microorganisms, develop and utilize medicinal resources, and systematically study the diversity of biodiversity and ecosystems. Given the structural differences and biodiversity of compounds derived from sponge symbiotic microorganisms, we believe that there are more resources waiting to be mined. We should make more efforts to study the pharmacodynamic relationships and pharmacological effects of promising compounds, and conduct clinical trials to complete the drug-like evaluation of the compound. The study on the chemical constituents of sponges and their co-existing microorganisms will promote the study of the relationship between sponges and their co-existing microorganisms, develop and utilize medicinal resources, and systematically study the diversity of biodiversity and ecosystems. Given the structural differences and biodiversity of compounds derived from sponge symbiotic microorganisms, we believe that there are more resources waiting to be mined.

Conflicts of Interest:
The authors declare no conflict of interest.

Conflicts of Interest:
The authors declare no conflict of interest.