A Brief Review of Bioactive Metabolites Derived from Deep-Sea Fungi

Deep-sea fungi, the fungi that inhabit the sea and the sediment at depths of over 1000 m below the surface, have become an important source of industrial, agricultural, and nutraceutical compounds based on their diversities in both structure and function. Since the first study of deep-sea fungi in the Atlantic Ocean at a depth of 4450 m was conducted approximately 50 years ago, hundreds of isolates of deep-sea fungi have been reported based on culture-dependent methods. To date more than 180 bioactive secondary metabolites derived from deep-sea fungi have been documented in the literature. These include compounds with anticancer, antimicrobial, antifungal, antiprotozoal, and antiviral activities. In this review, we summarize the structures and bioactivities of these metabolites to provide help for novel drug development.


Introduction
Fungi are well known for their vast diversity of secondary metabolites, which include many life-saving drugs and highly toxic mycotoxins [1]. Deep-sea fungi are the fungi that inhabit the sea and its sediment at a depth of over 1000 m below the surface [2]. Although the conditions in deep-sea environments are extreme and can be characterized by the absence of sunlight irradiation, predominantly human beings [40]. Therefore, seeking for high-efficiency, low-toxicity anticancer agents from deep-sea fungi has become one of the research subjects in the current pharmacy field.
An aromatic compound (84) ( Figure 12) has been isolated from the metabolites of the deep-sea sediment-derived Penicillium commune SD-118. It exhibits moderate cytotoxicity against the SW1990 cell line with IC50 of 0.11 mM [50].    (Figure 15), were isolated from the deep-sea fungus Aspergillus sydowi by a bioassay-guided method. All these compounds exhibit various degrees of cytotoxicity. Compounds 96 and 100 show strong cytotoxicity against P388 cells with IC50 of 0.14 and 0.59 μM, respectively [49].

Antibacterial
Antimicrobials are the most important drugs to protect human beings from infective diseases. Deep-sea fungi are one of the potential pools for screening antimicrobial metabolites, which can be developed into new drugs.

Citromycetin Analogue
A new citromycetin analogue, diorcinol (165) (Figure 26), has been isolated from the metabolites of Ascomycota sp. Ind19F07, which was collected from the deep-sea sediment in the Indian Ocean.
Based on in vitro tests, compound 165 shows strong antibacterial activity against both Gram-positive and -negative bacteria such as Acinetobacter baumanii, Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus [68].

Antiviral
Polyketides Although many polyketide compounds have been identified, the compounds derived from deep-sea fungi with antiviral activity are rare. Only one fungal hybrid polyketide with a new structure, cladosin C (171) (Figure 28), has been reported from the deep-sea fungus Cladosporium sphaerospermum 2005-01-E3. However, this compound shows good antiviral activity against influenza A H1N1 virus with an IC50 of 276 μM [9].

Hydroxyphenylacetic Acid
Compound 178 (Figure 30) has been reported from the deep-sea-derived fungus Aspergillus westerdijkiae SCSIO 05233 and shows strong antifouling activity with an EC50 of 8.8 mg/mL [57].

Antifungal
One compound, p-hydroxyphenopyrrozin (179) (Figure 31), with a new structure has been isolated from the deep-sea fungus Chromocleista sp. and characterized on the basis of mass spectroscopy, NMR experiments, derivatization, and X-ray crystallography studies. The MIC of this compound is 25 μg/mL against Candida albicans [1]. In 2013, Liu et al. reported a compound (180) ( Figure 31) that was isolated from the deep-sea fungus Aspergillus candidus and shows great growth inhibition against Candida albicans [67].

Conclusions
The fungi in deep-sea environments are very diverse and abundant, making them a versatile reservoir of metabolites with both new structures and bioactivities that can be of potential use, acting as leading compounds to synthesize new modern medicine. Although the research on deep-sea fungi is not as up-to-date as the research on fungi in other environments such as terrestrial soil, fresh water, and shallow marine areas due to difficulties in both sample collection and fungal cultivation methods, more and more fungi have been cultivated from the deep sea based on culture-dependent methods. These deep-sea fungi can provide a potential source for natural bioactive product screening and new drug discovery. Up to now, more than 180 new and/or bioactive secondary metabolites from deep-sea fungi with broad bioactivities, such as anticancer, antimicrobial, antifungal, anti-larval settlement, and antiviral, have been described in the literature. Most of the investigated bioactive compounds exhibit cytotoxic activity, then antimicrobial activity. These bioactive compounds not only help deep-sea fungi to defend themselves against predators in the natural ecosystem, but also have the potential of becoming treatments for human diseases and probes for new biological targets. Work to isolate fungi from deep-sea environments and characterize their bioactive metabolites is underway and is of increased importance due to the urgent need for new drugs to overcome emerging and drug-resistant diseases.