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Marine Compounds and their Antimicrobial Activities

M. J. Abad, L. M. Bedoya, P. Bermejo

Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, Avda. Complutense s/n, 28040, Madrid, Spain

Natural products have been regarded as important sources that could produce potential chemotherapeutic agents. In the search for new bioactive entities, investigations were expanded to marine habitats. Mankind has known for the last several thousand years that marine organisms contain substances capable of potent biological activity. However, the first serious investigation of marine organisms started only half a century ago. Since then, almost all forms of life in the marine environment (e.g., bacteria, algae, fungi, etc…) have been investigated for their natural product content. In the last several decades, plants, animals and microbes from the marine environment have revealed a portion of what is clearly a tremendous source of structurally diverse and bioactive secondary metabolites. Recent years have seen the introduction into clinical trials of new classes of chemotherapeutic agents, which are derived from marine sources and have novel mechanisms of action. Among other biological activities, the marine ecosystem is increasingly being acknowledged as a source of potential antimicrobial agents. Available treatments for many infectious diseases caused by bacteria, fungi and viruses are limited. Research on new antimicrobial substances must therefore be continued and all possible strategies should be explored. In this review, we will present the structures and antimicrobial activity of natural compounds isolated from marine sources from 2007 to the present.

Keywords marine environment; antibacterial; antifungal; antiviral

1. Introduction

Infectious diseases caused by bacteria, fungi and viruses are still a major threat to public health, despite the tremendous progress in human medicine. Their impact is particularly large in developing countries due to the relative unavailability of medicines and the emergence of widespread drug resistance. As a result of the continuous evolution of microbial pathogens towards antibiotic-resistance, there have been demands for the development of new and effective antimicrobial compounds. The term “antibiotic”, defined in 1942 by Selman A. Waksman, originally referred to any microbial product antagonistic to the growth of other microorganisms. In common usage today, “antibiotics” describes any compound that kills (microbicidal) or inhibits the growth (microstatic) of microorganisms. Most antimicrobials used clinically are either naturally-produced or resemble natural products. For example, of the twelve antibacterial classes, nine are derived from a natural product template. The molecular architectures of the β-lactams (penicillins, cephalosporins, carbapenems, monobactams), polyketides (tetracycline), phenylpropanoid (chloramphenicol), aminoglycosides (streptomycin), macrolides (erythromycin), glycopeptides (vancomycin), streptogramins (pristinamycin) and, most recently, the lipopeptides (daptomycin) and glycylcyclines (tegicycline) are borrowed from natural products. The other three classes, the sulfonamides, quinolones (ciprofloxacin) and oxazolidinones (linezolid), have no precedent in Nature. Following the discovery of most antimicrobial classes in the 1940s to 1960s, the so-called “Golden Age” of antimicrobial research, the arsenal of compounds for the treatment of microbial infections in humans was deemed sufficient. However, with the immediate development of antimicrobial resistance in microbes, this belief was quickly dispelled. Modern pharmaceutical development of antimicrobials has largely relied upon incremented semisynthetic modifications of natural products templates validated more than half a century ago. In fact, 73% of the antibacterial drugs approved between 1981 to 2005 encompassed only three classes, the β-lactams, macrolides and quinolones. This approach has produced molecules that narrowly, but temporarily, evade existing mechanisms of resistance. It seems obvious that only the discovery of new natural scaffolds that-by virtue of their chemical novelty-inhibit previously unknown microbial targets, can satisfy long-term concerns over microbial resistance. One solution to the global crisis of antibiotic resistance is the discovery of novel antimicrobial compounds for clinical application. Compared to the terrestrial environment, which was the focus of the pharmaceutical industry for more than 50 years, marine habitats have remained virtually unexplored for their ability to yield pharmacological metabolites. In the last several decades, research has expanded from land to ocean in order to find new leads for drug candidates. Because the ocean occupies almost 70% of Earth’s surface, it offers unlimited potential for biological and chemical diversity. Marine ecosystems comprise a continuous resource of immeasurable biological activities and vast chemical entities. Given such a background, the chemistry of marine natural products has been progressing at an unprecedented rate, resulting in a multitude of discoveries of carbon skeletons and molecules hitherto unseen on land. This diversity has provided a unique source of chemical compounds with potential bioactivities that could lead to potential new drugs candidates.

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A number of biologically active compounds with varying degrees of action, such as antitumour, anticancer, antimicrotubule, antiproliferative, cytotoxic, photoprotective, as well as antibiotic and antifouling properties, have so far been isolated from marine sources [1-3]. Some of these bioactive secondary metabolites of marine origin with strong antibacterial, antifungal and antiviral activities, are currently in intense use as antibiotics and may be effective against infectious diseases such as human immunodeficiency virus (HIV) and conditions of multiple bacterial infections (penicillin, cephalosporins, streptomycin and vancomycin). Marine organisms are under persistent threat of infection by resident pathogenic microbes including bacteria, and in response they have engineered complex organic compounds with antibacterial activity from a diverse set of biological precursors. The diluting effect of the ocean drives the construction of potent molecules that are stable to harsh salty conditions. Members of each class of metabolites, such as ribosomal and nonribosomal peptides, alkaloids, polyketides and terpenes, have been shown to exhibit antimicrobial and antiviral activity [4-6]. Almost all forms of invertebrates in the marine environment (e.g., sponges, algae, tunicates, bryozoans, molluscs,…) have been investigated for their natural product content. The marine environment also represents a largely unexplored source of isolation of new microbes (bacteria, fungi, microalgae-cyanobacteria and diatoms) that are potent producers of bioactive secondary metabolites. Extensive research has been done to unveil the bioactive potential of marine microbes (free living and symbiotic) and the results are amazingly diverse and productive [7, 8]. In this review, we will present the structures and antimicrobial activity of natural compounds isolated from the main marine organisms and microorganisms of interest (sponges, algae, bacteria and fungi) from 2007 to the present.

2. Marine organisms and microorganisms of interest

2.1 Sponges

Sponges, which appeared in the Cambrian period, are widely found from the coastal platform to deep waters and represent the oldest extant metazoan phylum, resembling in some features a common metazoan ancestor, the Urmetazoa. Sponges (phylum Porifera) are sessile marine filter feeders that have developed efficient defence mechanisms against foreign attackers such as viruses, bacteria or eukaryotic organisms. Marine sponges are among the richest sources of pharmacologically-active chemicals from marine organisms. It is suggested that (al least) some of the bioactive secondary metabolites isolated from sponges are produced by functional enzyme clusters, which originated from the sponges and their associated microorganisms. More than 5,300 different products are known from sponges and their associated microorganisms, and more than 200 new metabolites from sponges are reported each year. The chemical diversity of sponge products is remarkable. In addition to the unusual nucleosides, bioactive terpenes, sterols, peptides, alkaloids, fatty acids, peroxides and amino acid derivatives (all of them frequently halogenated) have been described from sponges. Their early appearance in evolution has given them considerable time for the development of an advanced chemical defence system. It is interesting to note that the synthesis of secondary metabolites is regulated according to the conditions that the sponge experiences. The huge number of different secondary metabolites discovered in marine sponges and the complexity of the compounds and their biosynthetic pathways can be regarded as an indication of their importance for survival. As infectious microorganisms evolve and develop resistance to existing pharmaceuticals, marine sponges provide novel leads against bacterial, fungal and viral diseases [9, 10].

2.2 Algae

Algae are very simple chlorophyll-containing organisms composed of one cell, grouped together in colonies or as organisms with many cells, sometimes collaborating together as simple tissues. They are found everywhere on earth: in the sea, rivers and lakes, on soil and walls, in animal and plants (as symbionts-partners collaborating together); in fact just about everywhere where there is a light to carry out photosynthesis. Algae are heterogeneous group of plants with a long fossil history. Two major types of algae can be identified: the macroalgae (seaweeds) occupy the littoral zone, which include green algae, brown algae and red algae, and the microalgae are found in both bentheic and littoral habitats and also throughout the ocean waters as phytoplankton. Phytoplankton comprise organisms such as diatoms (bacillariophyta), dinoflagellates (dinophyta), green and yellow-brown flagellates, and blue-green algae (cyanobacteria). As photosynthetic organisms, this group plays a key role in the productivity of oceans and constitutes the basis of the marine food chain. Marine algae produce a cocktail of metabolites with interesting biological activities (antiinfective, antiinflammatory, antiproliferative,…) and with potential commercial value [11-14]. Structures exhibited by these compounds range from acyclic entities with a linear chain to complex polycyclic molecules and included bioactive terpenes, phenolic compounds, alkaloids, polysaccharides and fatty acids. Their medical and pharmaceutical application has been investigated for several decades. Many of these secondary metabolites are halogenated, reflecting the availability of chloride and bromide ions in seawater [15]. Interestingly, bromide is more frequently used by algae for organohalogen production, although chlorine occurs in higher concentrations than bromine in seawater. Marine halogenated compounds comprise a varied assembly of molecules, ranging from peptides, polyketides, indoles, terpenes,

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acetogenins and phenols to volatile halogenated hydrocarbons. The prevalence of halogens is not similar in marine algae: chlorine and bromine appear to be the main halogens used to increase the biological activity of secondary metabolites, whereas iodine and fluorine remain quite unusual within the chemical structure. Macroalgae can be classified into three classes: green algae (Chlorophyta), brown algae (Phaeophyta) and red algae (Rhodophyta). Marine macroalgae or seaweeds have been used as foods, especially in China and Japan, and as crude drugs for treatment of many diseases such as iodine deficiency (goiter, Basedow’s disease and hyperthyroidism). Some seaweeds have also been used as a source of additional vitamins, treatment of various intestinal disorders, as vermifuges and as hypocholesterolaemic and hypoglycaemic agents. The characteristic green colour of green algae is mainly due to the presence of chlorophyll a and b in the same proportion as higher plants. The brown colour of brown algae is due to the dominance of the xanthophyll pigments and fucoxanthin; this masks the other pigments, chlorophyll a and b, β-carotenes and other xanthophylls. Brown algae represent a major component of littoral and sublittoral zones in temperate and subtropical ecosystems. An essential adaptative feature of this independent eukaryotic lineage is the ability to couple oxidative reactions resulting from exposure to sunlight and air with the halogenation of various substrates, thereby addressing various biotic and abiotic stresses, i.e., defence against predators, tissue repair, holdfast adhesion and protection against reactive species generated by oxidative processes. The food reserves of brown algae are typically complex polysaccharides and higher alcohols. The red colour of red algae is due to the dominance of the pigments phycoerythrin and phycocyanin; this masks the other pigments chlorophyll a (no chlorophyll b), β-carotene and a number of unique xanthophylls. The walls are made of cellulose, agars and carrageenans. Several red algae can be eaten. Marine eukaryotic microalgae are known to produce numerous useful products, but have attracted little attention in the search for novel antiinfective compounds. However, these reports concern mainly diatoms and cyanobacteria. Diatoms are ubiquitous and constitute an important group of the phytoplankton community, as well as masking an important contribution to the total marine primary production. These microalgae exhibit a characteristic golden-brown colour due to the high amount of the xanthophyll fucoxanthin which plays a major role in the light-harvesting complex of photosystems. In the water column, diatoms are exposed to light intensities that vary rapidly from lower to higher values. Diatoms produce an array of biologically active metabolites, many of which have been ascribed a form of chemical defence and which may have potential as candidate marine drugs. The blue-green algae (cyanobacteria) show many structural features in common with bacteria. However, they are classified with algae as they contain chlorophyll a and related compounds. These algae are ancient photosynthetic prokaryoytic organisms that produce biological active secondary metabolites with diverse chemical structures, such as nitrogenous compounds and cyclic polyethers [14]. One reason why marine cyanobacteria may have evolved this extensive capacity to produce such bioactive molecules is that they are prokaryotes that have developed beyond a microscopic lifestyle, and hence require an arsenal of defensive substances to ward off predation by diverse types of macrograzers. Recently, several marine cyanobacterial natural products have been the focus of much attention due to their intriguing structures and exciting biological activities [16].

2.3 Microorganisms

Microorganisms have been the source of many valuable compounds in medicine, industry and agriculture; most are derived from terrestrial habitats. After intensive studies on terrestrial microorganisms, consequent attentions have been focused on other ecosystems such as the sea. Marine microorganisms, including bacteria and fungi, are of considerable importance as promising new sources of a huger number of biologically active products [17-20]. Some of these marine species live in a stressful habitat, under cold, lightless and high pressure conditions. These factors have resulted in the development of unique metabolisms, which provide the opportunity to produce metabolites that differ from the terrestrial ones. Thus, sea microorganisms offer a wonderful resource for the discovery of new compounds with interesting biological activities, including antimicrobial and antiviral properties [8, 21]. Up until now, only a small number of microorganisms have been investigated for bioactive metabolites, yet a huge number of active substances have been isolated, some of which feature unique structural skeletons. In this section, we have surveyed the discoveries of products derived from marine sponges, algae, bacteria and fungi, which have shown efficacy or activity against infectious diseases, including bacterial, viral and fungal infections.

3. Anti-infective compounds

3.1 Terpenoids

Terpenoids are widely distributed in nature and are found in abundance in higher plants. Marine organisms are also a prolific source of unusual terpenoids. Natural terpenoids have dominated the subject of chemical ecology, and

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terpenoids have been assigned roles as phytoalexins, insect antifeedants and repellents, pollination attractants, defence agents against herbivores, pheromones, allelochemicals, plant hormones and signal molecules. Amongst the vast array of marine natural products, the terpenoids are one of the more commonly reported and discovered to date. During the formation of terpenoids, the isoprene units are usually linked in a head-to-tail manner, and the number of units incorporated into a particular unsaturated hydrocarbon terpenoid serves as a basis for the classification of these compounds: monoterpenoids (C10), sesquiterpenoids (C15), diterpenoids (C20), sesterterpenoids (C25), meroterpenoids (C26),… A survey of current available chemical data suggest that sesterterpenoids, sesquiterpenoids and meroterpenoids are the main classes of antimicrobial and antiviral terpenoids found in the marine environment. Marine sesterterpenoids are frequently occurring, particularly in marine sponges, and they show prominent bioactivities, including antimicrobial and antiviral properties [22]. Lee et al. [23] isolated seven sesterterpenes sulphates from the tropical sponge Dysidea sp., and investigated their inhibitory activities against isocitrate lyase from Candida albicans. Most of the compounds were found to be strong isocitrate lyase inhibitors, and also showed potent antibacterial effect against Bacillus subtilis and Proteus vulgaris. Another bioactive sesterterpenoid is hyrtiosal, isolated from the marine sponge Hyrtios erectus, which inhibits HIV integrase (IN) binding to viral DNA by a new inhibitor binding site [24]. Molecular dynamic analysis correlated with a site-directed mutagenesis approach further revealed that such hyrtiosal-induced viral DNA/IN binding inhibition was caused by the fact that hyrtiosal could bind HIV N-terminal domain at Ser17, Trp19 and Lys34. As hyrtiosal was recently discovered as a protein tyrosine phosphatase 1B inhibitor, this work might also supply multiple-target information for this marine natural product. Marine sponges are proving to be productive sources of many interesting active sesquiterpene-quinones/-hydroquinones. The 1,4-benzoquinone moiety is a common structural feature in a large number of compounds that have received considerable attention owing to their broad spectrum of biological activities, including antimicrobial and antiviral properties. Puupehanol is a new sesquiterpene-dihydroquinone derivative isolated from the marine sponge Hyrtios sp., along with the known compounds puupehenone and chloropuupehenone, that are responsible for the antifungal activity observed in the sponge extract [25]. Of the compounds tested, puupehenone exhibited the most potent inhibitory activity against Cryptococcus neoformans and Candida krusei, with minimum inhibitory concentration (MIC) of 1.25 to 2.50 μg/ml, respectively. Examples of other antimicrobial sesquiterpenoid-quinones from marine sponge origin also included nakijiquinones G-I isolated from Okinawan marine sponges of the family Spongilidae [26], and new sesquiterpenoid-hydroquinones from the marine sponge Dysidea arenaria, which exhibited moderate inhibitory activity on HIV reverse transcriptase (RT) [27]. These type of compounds have also been isolated from marine algae. Peyssonoic acid A and B, novel sesquiterpene-hydroquinones, were isolated from the crustose red alga Peyssonnelia sp [28]. At ecologically realistic concentrations, both compounds inhibited growth of Pseudoalteromonas bacteriolytica, a bacterial pathogen of marine algae, and Lindra thalassiae, a fungal pathogen of marine algae. The peyssonoic acids included one novel carbon skeleton and illustrated the utility of ecological studies in the discovery of natural products. Antimicrobial sesquiterpenoid-hydroquinones occasionally incorporated halogens, such as tiomanene and acetylmajapolene A and B isolated from Malaysian Laurencia sp. [29], and the new brominated metabolite 10-hydroxykahukuene B isolated from the red marine alga Laurencia mariannensis [30]. Reports of other antimicrobial terpenoids isolated from marine sponges also included meroterpenoids. During an investigation aimed at discovering new antimicrobial agents from marine organisms, Zhang et al. [31] isolated fascioquinols A-F as bioactive meroterpenes from a deep-water southern Austalian marine sponge Fasciospongia sp. Fascioquinols B, C and D are a series of new acid mediated hydrolysis/cyclization products of fascioquinol A. Two of these compounds, fascioquinol A and B displayed promising Gram (+) selective antibacterial activity against Staphylococcus aureus (inhibitory concentration 50 IC50 0.9-2.5 μM) and Bacillus subtilis (IC50 0.3-7 μM). Four new meroterpenes, alisiaquinones A-C and alisiaquinol were isolated from a New Caledonian deep water sponge [32]. The compounds displayed μM range activity on two enzymatic targets of importance for the control of malaria, the plasmodial kinase Pfnek-1 and a protein farnesyl transferase, as well as on different chloroquine-sensitive and –resistant strains of Plasmodium falciparum. Examples of another antimicrobial terpenoid of marine sponge origin also included diterpene and diterpene isonitriles from the tropical marine sponge Cymbastela hooperi [33]. Antiviral diterpenes have also been isolated from marine algae. Abrantes et al. [34] isolated the diterpenes 8,10,18-trihydroxy-2,6-dolabelladiene and (6R)-6-hydroxydichotoma-4,14-diene-1,17-dial from the Brazilian brown algae Dictyota pfaffi and Dictyota menstrualis. The compounds inhibited herpes simplex type-1 (HSV-1) replication in Vero cells. The first compound sustained its anti-herpetic activity even when added to HSV-1 infected cells at 6h after infection, while the second compound sustained its activity for up to 3h after infection, suggesting that these compounds inhibit initial events during HSV-1 replication. These results suggest that the structures of both compounds, Brazilian brown algae diterpenes, might be promising for future antiviral design. These algae also yielded the dolabellane diterpene dolabelladienetriol as a typical non-competitive inhibitor of HIV RT enzyme [35]. Kamei et al. [36] screened extracts of 342 species of marine algae collected from Japanese coastlines for antibacterial activity against Propionibacterium acnes, and found a novel antibacterial compound, the diterpene sargafuran, from the methanolic extract of the marine brown alga Sargassum macrocarpum. Sargafuran was bactericidal and completely



killed Propionibacterium acnes by lysing bacterial cells. These results suggest that sargafuran might be useful as a lead compound to develop new types of anti-Propionibacterium acnes substances and new skincare cosmetics to prevent or improve acnes. Examples of other antibacterial diterpenes from marine origin also included dehydroxychlorofusarielin B, a polyoxygenated decalin derivative from the marine-derived fungus Aspergillus sp., which exhibited antibacterial activity against Staphylococcus aureus and methicillin- and multidrug-resistant Staphylococcus aureus [37].

3.2 Steroids

Steroid glycosides are a class of widespread natural products having either terrestrial or marine origins. Several cardiac glycosides are used therapeutically in the treatment of cardiac failure and atrial arrhytmias, and many glycoside compounds, belonging to other structural groups, show cytotoxic, antimicrobial, hypocholesterolemic and other biological activities. Most marine steroid glycosides were isolated not from pants, but from invertebrates such as echinoderms, sponges and soft corals, and are one of the most important chemical constituents of microalgae [38]. Phytochemical and pharmacological studies have been undertaken in order to reveal the presence of steroids with antimicrobial activity. These reports mainly concerned their antifungal activity. Eurysterols A and B are two new steroidal sulphates isolated from an undescribed marine sponge of the genus Euryspongia collected in Palau [39]. The compound exhibited antifungal activity against amphotericin B-resistant and wild-type strains of Candida albicans, with MIC values in turn of 15.6 and 62.5 μg/ml. Bioassay-guided fractionation of the extract of Topsentia sp. led to the identification of two new sulphated sterols, geodisterol-3-O-sulphite and 29-demethylgeodisterol-3-O-sulphite, as active constituents reversing efflux pump-mediated fluconazole resistance [40]. Both compounds enhanced the activity of fluconazole in a Saccharomyces cerevisiae strain overexpressing the Candida albicans efflux pump MDR1, as well as in a fluconazole-resistant Candida albicans clinical isolate known to overexpress MDR1. Examples of other antimicrobial steroids from marine origin also included bile acid derivatives from the sponge-associated bacterium Psychrobacter sp. [41], and ring B aromatic steroids from the marine endophytic fungus Colletotrichum sp., which showed antimicrobial activity against the fungus Microbotryum violaceum, and the bacteria Escherichia coli and Bacillus megaterium [42].

3.3 Phenolic compounds

Phenols probably constitute the largest group of plant secondary metabolites. Widespread in nature, and found in most classes of natural compounds having aromatic moieties, they range from simple structures with one aromatic ring to highly complex polymeric substances. Phenolic compounds, occasionally incorporating halogen, occur frequently in marine environment. In recent years, a large number of studies have been performed concerning the antimicrobial activity of phenolic compounds isolated from marine sponges, mainly antibacterial activity. 2-(2’,4’-dibromophenoxy)-4,6-dibromophenol isolated from the marine sponge Dysidea granulosa collected off the coast of Lakshadweep Islands, Indian Ocean, exhibited potent and broad spectrum in vitro antibacterial activity, especially against methicillin-resistant and –sensitive Staphylococcus aureus, vancomycin-resistant and –sensitive Enterococci and Bacillus sp [43]. From another Dysidea species collected from the Federated States of Micronesia, a new polybrominated diphenyl ether was isolated [44]. These compounds exhibited inhibitory activities against Streptomyces 85E in the hyphae formation inhibition assay. These type of compounds were also isolated from the Indonesian sponge Lamellodysidea herbacea [45]. These metabolites showed potent antimicrobial activity against Bacillus subtilis. For the studies of structure-activity relationships, it can be deduced that the presence of two phenolic hydroxyl groups and bromines at C-2 and/or C-5 is important for the exhibition of antibacterial activity. Bromophenol compounds have frequently been encountered in other marine organisms and microorganisms, including red algae and bacteria. Some of these compounds have been isolated by bioassay-guided fractionation after previously detecting activity on the marine extracts. In the course of the search for biologically active constituents from marine algae, Oh et al. [46] collected Odonthalia corymbifera, whose crude extracts exhibited antimicrobial activity against various microorganisms. Bioassay-guided separation of the crude extract afforded several bromophenol compounds. Among the isolated natural products, 2,2’,3,3’-tetrabromo-4,4’,5,5’-tetrahydroxydiphenylmethane was found to be the most active derivative against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum and Trichophyton mentagrophytes. These type of compounds have also been reported from marine bacteria, such as 4,4’,6-tribromo-2,2’-biphenol isolated from an extract of a marine Pseudoalteromonas sp. CMMED 290, which displayed significant antimicrobial activity against methicillin-resistant Staphylococcus aureus [47]. From another Pseudoalteromonas species, the marine bacterium Pseudoalteromonas phenolica O-BC30T, Isnansetyo and Kamei [48] isolated 2,2’,3-tribromo-biphenyl-4,4’-dicarboxylic acid. The compound exhibited anti-methicillin-resistant Staphylococcus aureus activity against all ten clinical isolates of these microorganisms, with MIC values between 1 and 4 μg/ml. The compound was also highly active against Bacillus subtilis and Enterococcus serolicida, but was inactive against Gram (-) bacteria and fungi. These

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results demonstrated that this bromophenyl compound has high in vitro activity against methicillin-resistant Staphylococcus aureus and might be useful as a lead compound in developing new antimicrobial substances. Other antimicrobial bromophenyl compounds have also been isolated from the marine bacterium Pseudoalteromonas haloplanktis INH strain [49]. Reports of other antimicrobial phenolic compounds isolated from the marine environment also included anthraquinones, coumarins and flavonoids. Some of these compounds have been isolated by bioassay-guided fractionation after previously detecting activity on the marine extracts. As part of an ongoing search for bioactive metabolites from the fungus Arpergillus versicolor derived from a marine sponge Petrosia sp., five anthraquinones were isolated by bioactivity-guided fractionation [50]. Some of these compounds exhibited antibacterial activity against several clinically isolated Gram (+) strains with MIC values of 0.78-6.25 μg/ml. From another Aspergillus species, the marine-derived fungus Aspergillus sp. strain 05F16 collected at the coral reef of Manado, Indonesia, two new hexahydroanthrones, tetrahydrobostrycin and 1-deoxytetrahydrobostrycin were isolated [51]. Tetrahydrobostrycin showed weak antibacterial activity against Staphylococcus aureus and Escherichia coli, and 1-deoxytetrahydrobostrycin against Staphylococcus aureus. Monodictyoquinone A (1,8-dihydroxy-2-methoxy-6-methylanthraquinone) is a new antimicrobial anthraquinone from a sea urchin-derived fungus Monodictys sp. [52]. These type of compounds have also been reported from the marine bacterium Nocardia sp. ALAA 2000, which was isolated from the marine red alga Laurencia spectabilis collected off the Ras-Gharib coast of the Red Sea, Egypt [53]. These compounds displayed different potent antimicrobial activity against both Gram (+) and Gram (-) bacteria as well as fungi with MIC ranging from 0.1 to 10 μg/ml. El Gendy et al. [54] isolated three phenolic compounds, 7-methylcoumarin, and two flavonoids, rhamnazin and cirsimaritin, from a marine Streptomyces sp. The isolated compounds are reported to be antimicrobial products. Examples of other antimicrobial phenolic compounds from marine origin also included ammonificins A and B, chroman derivatives from the marine hydrothermal vent bacterium Thermovibrio ammonificans [55], phlorotannins from the edible seaweed Ecklonia cava [56], and new sulfoalkylresorcinol from the marine-derived fungus Zygosporium sp. KNC52, which exhibited antimicrobial activity against multidrug-resistant bacteria [57].

3.4 Alkaloids

Alkaloids represents a group of natural products that has had a major impact throughout history on the economic, medical, political and social affairs of humans. Alkaloids are difficult to define because they do not represent a homogeneous group of compounds from either the chemical, biochemical or physiological viewpoint. Consequently, except for the fact that they are all nitrogenous compounds with a limited distribution in nature, reservations must be appended to any general definition. Marine organisms and microorganisms are known to be a rich source of alkaloids with unique chemical feature and pronounced chemical activities, all of which suggests their potential value as lead structures for the development of new pharmaceuticals. Many of these compounds have potential pharmacological effects, including antimicrobial and antiviral properties. Marine sponges are proving to be productive sources of many interesting antimicrobial active nitrogen-containing heterocyclic compounds, including alkylpiperidine, bromopyrrole and pyrroloiminoquinone alkaloids. In the search for antimicrobial agents against dormant Mycobacterium tuberculosis, halicyclamine A was re-discovered as a lead for anti-tuberculosis agent from a marine sponge of Haliclona sp. on the guidance of the constructed bioassay [58]. Halicyclamine A showed growth inhibition against Mycobacterium smegmatis, Mycobacterium bovis and Mycobacterium tuberculosis, with MIC in the range of 1-5 μg/ml under both aerobic condition and hypoxic condition inducing dormant state. The growth-inhibitory activity of halicyclamine A was bactericidal and did not exhibit cross-resistance with the currently used anti-tuberculosis drugs of isoniazid, ethambutol, rifampicin and streptomycin. More recently, this sponge yielded a new tetracyclic alkylpiperidine alkaloid, 22-hydroxyhaliclonacyclamine B, together with two known alkaloids, haliclonacyclamine A and B as anti-dormant mycobacterial substances [59]. For the studies of structure-activity relationships, it can be deduced that the 22-hydroxy group in position 1 was found to reduce anti-mycobacterial activity, because 22-hydroxyhaliclonacyclamine B exhibited weaker antimicrobial activities against Mycobacterium tuberculosis. Examples of other antimicrobial alkaloids from Haliclona sp. also included haliclonin A, which exhibited antibacterial activity against diverse microbial strains [60]. Other antimicrobial alkaloids from marine sponges are bromopyrrole alkaloids, which are known to be some of the most common metabolites contained in these organisms. These type of compounds, such as nagelamides Q, R, J, K, L, M and N have been isolated as antimicrobial constituents from the sponge Agelas sp [61-64]. Nagelamide Q is a rare dimeric bromopyrrole alkaloid possessing a pyrrolidine ring, while nagelamide R is the first bromopyrrole alkaloid having an oxazoline ring. One of these compounds, nagelamide J is the first bromopyrrole alkaloid possessing a cyclopentane ring fused to an amino imidazole ring. More recently, benzosceptrin C, a new dimeric bromopyrrole alkaloid possessing a benzocyclobutane ring, has been isolated from an Okinawan marine sponge of this genus as antimicrobial constituent [65]. Another bromopyrrole alkaloid, oroidin, has been isolated from the Turkish sponge Agelas oroides [66]. The compound inhibits the enoyl reductases from Plasmodium falciparum, Mycobacterium



tuberculosis and Escherichia coli, and represents the first marine metabolite that inhibits the enoyl-ACP reductase, a clinically relevant enzyme target from the type II fatty acid pathway of several pathogenic microorganisms. Several compounds related to bromopyrrole alkaloids have also been isolated from marine bacteria. Cultivation of an obligate marine Streptomyces strain has furnished the marinopyrroles A and B, densely halogenated axially chiral metabolites that contain an uncommon bispyrrole structure [67]. The marinopyrroles possess potent antibiotioc activities against methicillin-resistant Staphylococcus aureus. Other halogenated alkaloids from marine origin are the bromotyrosine alkaloids ceratinadins A-C isolated from an Okinawan marine sponge Pseudoceratina sp., which possess an N-imidazolyl-quinolinone moiety and showed antifungal activity [68]. From another Pseudoceratina sponge species, Pseudoceratina purpurea, Jang et al. [69] isolated pseudoceratins A and B, two bicyclic bromotyrosine-derived metabolites, which exhibited significant antifungal activity against Candida albicans. Jeon et al. [70] isolated two new pyrroloiminoquinone alkaloids of the discorhabdin class from the sponge Sceptrella sp. collected from Gageodo, Korea. These compounds exhibited moderate to significant antibacterial activity and inhibitory activity against sortase A, an enzyme that plays a key role in cell wall protein anchoring and virulence in Staphylococcus aureus. Fasciospongins A and B are two unusual sulphated sesterterpene alkaloids of an unprecedented structural class that have been isolated from the marine sponge Fasciospongia sp [71]. The compounds displayed potent inhibitory activity to Streptomyces 85E in the hyphae-formation inhibition bioassay. More recently, two new sulphated sesterterpene alkaloids, 19-oxofasciospongine A and fasciospongine C, and a new sesterterpene sulphate, 25-hydroxyhalisulphate 9, along with two known sesterterpenes sulphates, halisulphates 7 and 9, were isolated from an organic extract of the marine sponge Fasciospongia sp. [72]. Some of these compounds also exhibited inhibitory activity against Streptomyces 85E in the hyphae-formation inhibition assay. Other sulphated alkaloids are baculiferins A-O, O-sulphated pyrrole alkaloids from the Chinese marine sponge Iotrochota baculifera [73]. Baculiferins C, E-H and K-N were found to be potent inhibitors against the HIV IIIB in both MT4 and MAGI cells. Additional bioassay revealed that baculiferins could dramatically bind to the HIV target protein’s viral infectivity factor (Vif), the cellular deoxycytidine deaminase APOBEC3G and the recombinant gp41, a trans-membrane protein of HIV. A number of polycyclic guanidine alkaloids have been reported from Monanchora unguifera with noteworthy antiviral and antimicrobial activities [74]. Batzelladine alkaloids, such as 16β-hydroxycrambescidin 359, batzelladines K, L, M and N, ptilomycalin A, crambescidine 800, batzelladine C and dehydrobatzelladine C were isolated from this Caribbean sponge. The compounds showed significant activities against HIV, and acquired immunodeficiency syndrome (AIDS) opportunistic infections patghogens. More recently, merobatzelladines A and B have been isolated from this marine sponge as an antibacterial constituent [75]. Marine sponges are proving to be productive sources of many interesting antimicrobial active nitrogen-containing heterocyclic compounds, including 1H-benzo[de][1,6]-naphthyridine alkaloids. Souza et al. [76] demonstrated that the alkaloid 4-methylaaptamine isolated from the marine sponge Aaptos aaptos inhibited HSV-1 replication in Vero cells in a dose-dependent manner, with an effective concentration 50 (EC50) value of 2.4 μM. These studies also found that 4-methylaaptamine sustained antiherpetic activity even when added to HSV-1 infected Vero cells at 4h after infection, suggesting that this compound inhibits initial events during HSV-1 replication and impairs HSV-1 penetration without affecting viral adsorption. This sponge also yielded four aaptamines with inhibitory activity against sortase A, an enzyme that plays a key role in cell wall protein anchoring and virulence in Staphylococcus aureus [77]. The suppression of fibronectin-binding activity by one of these compounds, isoaaptamine, highlights its potential for the treatment of Staphylococcus aureus infections via inhibition of sortase A activity. Other antimicrobial alkaloids from marine sponges are bisindole alkaloids of the topsentin and hamacanthin classes isolated from the methanolic extract of a marine sponge Spongosorites sp. by bioactivity-guided fractionation [78]. One of these compounds, (R)-6’-debromohamacanthin B showed weak antibacterial activity against clinically isolated methicillin-resistant strains. Examples of other antimicrobial alkaloids isolated from marine sponges also included two new alkaloids, dysideanins A and B from the South China marine sponge Dysidea sp. [79], and 5-hydroxyindole-type alkaloids from the tropical sponge Hyrtios sp., which showed Candida albicans isocitrate lyase inhibitory activity [80]. In cyanobacteria, one family of alkaloids that has been explored for their pharmaceutical potential are isonitrile-containing indole alkaloids, such as hapalindoles. All of these alkaloids have polycyclic carbon skeletons that derive from condensation of a tryptophan derivative and geranyl pyrophosphate. The promising biological activities and intricate structures have led to several synthetic efforts for this class of alkaloids. These type of compounds, such as fischambiguines A and B, ambiguine P, ambiguine Q nitrite as well as ambiguine G nitrite were identified from the cultured cyanobacterium Fischerella ambigua [81]. The alkaloids possessed fused pentacyclic and hexacyclic carbon skeletons. Fischambiguine B displayed a strong inhibitory activity against Mycobacterium tuberculosis, with an MIC value of 2 μM. Other type of marine antimicrobial alkaloids included diketopiperazine alkaloids. Some of these compounds have been isolated by bioassay-guided fractionation, after previously detecting activity on the marine extracts. In order to search for structurally novel and bioactive natural compounds from marine-derived fungi, a halotolerant fungal strain (THW-18) identified as Alternaria raphani was isolated from sediment collected in the Hongdao sea salt fields. From

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the ethyl acetate extract of this marine fungus, three new cerebrosides, alternarosides A-C, and a new diketopiperazine alkaloid, alternarosin A, were isolated [82]. These compounds showed weak antibacterial activity against Escherichia coli, Bacillus subtilis and Candida albicans, with MIC values ranging from 70 to 400 μM. Examples of other antimicrobial alkaloids from marine sponge origin also included caboxamycin produced by the deep-sea strain Streptomyces sp. NTK937, which showed inhibitory activity against Gram (+) bacteria [83].

3.5 Polysaccharides

Polysaccharides are polymers of monosaccharides (sugars) linked together through glycosidic (ether) linkages, and represent a structurally diverse class of biological macromolecules. The structural diversity of these compounds arises from the many different sugars and sugar derivatives such as uronic acid found in polysaccharides, and because each sugar can be covalently linked to other sugar through several different positions at the sugar ring. They are used extensively as foods and pharmaceuticals. The enormous variety of polysaccharides that can be extracted from marine plants and animal organisms, or produced by marine bacteria and fungi, means that the field of marine polysaccharides is constantly evolving [84]. Some of these marine polysaccharides showed interesting antimicrobial and antiviral activity. The acidic polysaccharide nostoflan was isolated as an antiviral component (anti-HSV-1) from the edible blue-green alga Nostoc flagelliforme [85] In time-of-addition experiments, the most sensitive stage of viral replication to nostoflan was found to be early events, including the virus binding and/or penetration processes. In order to determine to what extent nostoflan may be involved in these processes, virus binding and penetration assays were separately performed. The results indicate that the inhibition of virus binding to-but not penetration into-host cells was responsible for the antiherpetic effect induced by nostoflan. Another antiviral polysaccharide from marine origin is a lectin isolated from the filamentous cyanobacterium Oscillatoria agardhii NIES-204, which potently inhibits HIV replication in MT-4 cells [86]. These marine polysaccharides also showed antifungal activity, such as a chitinase isolated from a marine Streptomyces sp. DA11 associated with the South China sea sponge Craniella australiensis which showed antifungal activity against Aspergillus niger and Candida albicans [87]. The sponge’s microbial symbiont with chitinase activity may contribute to chitin degradation and antifungal defence.

3.6 Peptides

The ubiquitous presence of antimicrobial peptides and proteins in marine environment attests to their overall importance in building the defence strategies of most organisms. They are considered part of the humoral natural defence of invertebrates against infections and have thus also been termed “natural antibiotics” [88, 89]. A number of peptides from marine sponges with antimicrobial and antiviral activities have been identified in recent years, such as cyclodepsipeptides [90]. The structural characteristic of this family of cyclic peptides include various unusual amino acid residues and unique N-terminal polyketide-derived moieties. Papuamides are representatives of a class of marine sponge derived cyclic depsipeptides, which are thought to have cytoprotective activity against HIV in vitro, by inhibiting viral entry. From the sponge Siliquariaspongia mirabilis, four new cyclic depsipeptides termed mirabamides A-D have been isolated as antiviral constituents [91]. The compounds have been shown to potently inhibit HIV fusion. Mirabamides contain two new entities, including 4-chloromoproline in 1-3 and an unusual glycosylated amino acid, β-methoxytyrosine 4’-O-α-L-rhamnopyranoside (in 1, 2 and 4), along with a rare N-terminal aliphatic hydroxy acid. Mirabamide A inhibited HIV in neutralization and fusion assays with IC50 values between 40 and 140 nM, as did mirabamides C and D (IC50 values between 140 nM and 1.3 μM for C and 190 nM and 3.9 μM for D), indicating that these peptides can act at the early stages of HIV-entry. Additionally, mirabamides A-C inhibited the growth of Bacillus subtilis and Candida albicans at 1-5 μg/disk in disk diffusion assays. A cyclic depsipeptide such as alternaramide was also isolated from the marine-derived fungus Alternaria sp. SF-5016 [92]. The compound showed weak antibiotic activity against Bacillus subtilis and Staphylococcus aureus. Another anti-HIV cyclodepsipeptide is homophymine A, isolated from a New Caledonian collection of the marine sponge Homophymia sp. [93]. In a cell-based 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, homophymime A exhibited cytoprotective activity against HIV infection with a IC50 of 75 nM. The compound contains eleven amino acid residues and an amide-linked-3-hydroxy-2,4,6-trimethyloctanoic acid moiety. Along with four D-, two L- and one N-methyl amino acids, it also contains four unusual amino acid residues. Examples of other antimicrobial and antiviral peptides from marine sponge origin also included callyaerins A-F and H from the Indonesian marine sponge Callyspongia aerizusa [94], and theonellamides, antifungal bicyclic peptides derived from marine sponges [95]. Other antimicrobial peptides found in the marine environment are aminolipopeptides. Three new aminolipopeptides, designated trichoderins A, A1 and B, were isolated from a culture of marine sponge-derived fungus of Trichoderma sp. as anti-mycobacterial substances with activity against active and dormant bacilli [96]. Trichoderins showed potent anti-mycobacterial activity against Mycobacterium smegmatis, Mycobacterium bovis and Mycobacterium tuberculosis under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions, with MIC values in the range of



0.02-2 μg/ml. Additionally, two novel cyclic hexapeptides containing both anthranilic acid and dehydroamino acid units, sclerotides A and B, were isolated from the marine-derived halotolerant Aspergillus sclerotiorum PT06-1 [97]. Both compounds showed antifungal and antibacterial activity. This fungus, Aspergillus sclerotiorum PT06-1, also yielded the new aspochracin-type cyclic tripeptides sclerotiotides A-K [98]. Some of these compounds, such as sclerotiotides A, B, F and I showed selective antifungal activity against Candida albicans. Reports on the isolation of antimicrobial peptides from marine bacteria have also been found in the literature. Zhang et al. [99] isolated two new cyclic lipopeptides, maribasins A and B, from the fermentation broth of the marine microorganisms Bacillus marinus B-9987 isolated from Suaeda salsa on the Bohai coastline of China. The compounds exhibited broad-spectrum activity against phytopathogens by the antifungal bioassay. Another Bacillus species, Bacillus amyloliquefaciens SH-B10 isolated from deep-sea sediments, produces two antifungal lipopeptides that were purified by bioactivity-guided fractionation [100]. Both compounds showed significant inhibitory activities against five plant fungal pathogens in paper-agar disk diffusion assay. This is the first report on the antifungal activities of the rare 6-Abu fengycin lipopeptides, and at the same time provided an insight into the potential of marine microbial resource in biological control and sustainable agriculture. From the marine bacterial isolate Brevibacillus laterosporus PNG276 obtained from Papua New Guinea, tauramamide, a new lipopeptide, has been isolated [101]. Tauramamide and ethyl ester 3 show potent and relatively selective inhibition of pathogenic Enterococcus sp. Other antimicrobial peptides from marine bacterium origin are thiopeptides and depsipeptides. Some of these compounds have been isolated by bioassay-guided fractionation after previously detecting activity in the marine extract. Activity-guided fractionation of fermentation extracts of the marine Nocardiopsis sp. TP-1161 allowed the identification and purification of the active compound [102]. Structure elucidation revealed this compound to be a new thiopeptide antibiotic with a rare aminoacetone moiety. The in vitro antibacterial activity of this thiopeptide against a panel of bacterial strains was determined. Unnarmicine A and C are new antibacterial depsipeptides produced by marine bacterium Photobacterium MBIC06485 [103]. Both compounds selectively inhibited the growth of two strains belonging to the genus Pseudovibrio, one of the most prevalent genera on the marine environments. Other antimicrobial peptides found in the marine environment are hybrid polyketide-nonribosomal peptide antibiotics. Marine myxobacteria are rare culture-resistant microorganisms, several strains of which have been identified by research groups in Asia. Paraliomyxa miuraensis, a slightly halophilic myxobacterium discovered in Japan, produces the cyclic hybrid polyketide-peptide antibiotics known as miuraenamides A and B [104]. The structure-antimicrobial activity relationships of these compounds, demonstrated the importance of both the macrocyclic structure and the β-methoxyacrylate moiety. Ariakemicins A and B are unusual linear hybrid polyketide-nonribosomal peptide antiobiotics from a marine gliding bacterium of the genus Rapidithrix [105]. The ariakemicins were composed of threonine, two Ω-amino-(Ω-3)-methyl carboxylic acids with diene or triene units, and δ-isovanilloylbutyric acid. The antibiotics selectively inhibited the growth of Gram (+) bacteria. Examples of other antimicrobial peptides from marine origin also included nonribosomal peptides produced by Brazilian cyanobacterial isolates [106], and those produced by Brevibacillus laterosporus Lh-1 isolated from the sea sediment, which showed antimicrobial activity against Gram (+) and Gram (-) bacteria and fungus [107].

3.7 Polyketides

Polyketides are an important class of secondary metabolites with an enormous impact in the pharmaceutical industry due to their high commercial value. The macrolide antibiotics amphotericin, nystatin and rapamycin are famous examples of this class of natural products employed in human therapy as immunosuppressant, antibiotics and antifungals. Phytochemical studies showed the ability of marine sponges to produce and store polyketide as polycyclic ether macrolides and open-chain polyketides. Some of these compounds showed strong antimicrobial and antiviral activities, and have been isolated by bioassay-guided fractionation after previously detecting activity on the sponge extracts. Bioassay-directed fractionation of South Pacific marine sponges of the genus Xestospongia, has led to the isolation of a number of halenaquinone-type polyketides, including two new derivatives named xestosaprol C methylacetal 7 and orholquinone 8 [108]. Orholquinone 8 displayed a significant inhibition of both human and yeast farnesyl transferase enzymes, with IC50 value of 0.40 μM, and was a moderate growth inhibitor of Plasmodium falciparum. A new marine-derived macrolide designated neopeltolide, has been isolated from a deep-water sponge of the family Neopeltidae [109]. The compound inhibited the growth of the fungal pathogen Candida albicans, with a MIC of 0.62 μg/ml. Other antifungal polyketides are 7-O-methylkoninginin D and trichodermaketones A-D isolated from the marine-derived fungus Trichoderma koningii, which showed synergistic antifungal activity against Candida albicans, with 0.05 μg/ml-ketoconazole [110]. Trichodermaketones A and B are unprecedented polyketides with a bistetrafuran-containing tricyclic skeleton. A new 24-membered macrolide, macrolactin T, and a new polyene δ-lactone, macrolactin U, along with macrolactins A, B, D, O and S were isolated from the cultured broth of the bacterium Bacillus marinus, which was isolated from Suaeda salsa collected on the coastline of Bohai sea of China [111, 112]. Macrolactins T, B and O showed inhibitory activity against fungi Pyricularia oryzae and Alternaria solani, and bacteria Staphylococcus aureus. Examples of other antimicrobial polyketides found in the marine environment also included curvularin and α,β-

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dehydrocurvularin isolated from the ethyl acetate extract of the fungus Eupenicillium sp. associated with the marine sponge Axinella sp. [113]. From another marine-derived fungus, Penicillium sp. PSU-F44, Trisuwan et al. [114] isolated the macrolides (+)-brefeldin A, (+)-brefeldin C and 7-oxobrefeldin A, which showed antimicrobial activity against methicillin-resistant Staphylococcus aureus and Microsporum gypseum, while the marine-derived fungus Nigrospora sp. PSV-F18 and PSU-F5 also yielded the antimicrobial macrolides nigrosporapyrones A-D and nigrospoxydons A-C [115, 116].

3.8 Fatty acids

Fatty acids with two or more methylene-interrupted double bonds are essential for normal cell function, and have entered the biomedical and nutraceutical areas as a result of the elucidation of their biological role in certain clinical conditions common in Western society, such as obesity and cardiovascular diseases. Marine fatty acids are of interest for the different roles and biological properties they exhibit in the cells of marine organisms. Some of these fatty acids have displayed interesting biological activities, including antimicrobial and antiviral properties. A new acetylenic fatty acid has been isolated from the calcareous sponge Paragrantia cf. waguensis [117]. The compound showed antimicrobial activity against Staphylococcus aureus and Escherichia coli, with MIC of 64 and 128 μg/ml, respectively. Examples of other antimicrobial fatty acids from marine sponge origin also included brominated unsaturated fatty acids from a marine sponge collected in Papua New Guinea [118], and motualevic acids A-F isolated from the sponge Siliquariaspongia sp., which inhibit the growth of Staphylococcus aureus and its methicillin-resistant strains [119]. Antimicrobial fatty acids have also been isolated from marine algae. Extracts from the marine diatom Phaeodactylum tricornutum have antibacterial activity. Desbois et al. [120] isolated and identified the antibacterial compounds responsible for this activity such as the monounsaturated fatty acid (9Z)-hexadecenoic acid, and the relatively unusual polyunsaturated fatty acid (6Z,9Z,12Z)-hexadecatrienoic acid. Both compounds are active against Gram (+) bacteria with further inhibitory activity to the growth of the Gram (-) marine pathogen Listonella anguillarum. The first compound is active at μM concentrations, kills bacteria rapidly and is highly active against multidrug-resistant Staphylococcus aureus. More recently, this diatom also yielded a new antibacterial fatty acid, eicosapentaenoic acid, which is active against a range of both Gram (+) and Gram (-) bacteria, including multiresistant-Staphylococcus aureus [121]. Asperamides A and B, a sphingolipid and their corresponding glycosphingolipid possessing a hitherto unreported 9-methyl-C20-sphingosine moiety, were characterized from the culture extract of Aspergillus niger EN-13, an endophytic fungus isolated from the marine brown alga Colpomenia sinuosa [122]. In the antifungal assay, asperamide A displayed activity against Candida albicans. Marine fungi are of great importance as potential sources of agricultural pesticide leads. These compounds belong to different structural classes, including fatty acids. For example, unsaturated fatty acid glycerol esters, asperxanthone and asperbiphenyl, were isolated from a selected marine fungus identified as Aspergillus sp. MF-93 collected in the Quan-Zhou Gulf [123]. The compound showed inhibitory activity against tobacco mosaic virus, a typical member of the tobamovirus group of plant viruses.

Acknowledgements This work was supported by Ministerio de Asuntos Exteriores y de Cooperación (D/031518/10). The technical assistance of Ms. Brooke-Turner is gratefully acknowledged.

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