Download Marine Compounds and their Antimicrobial Activities

Science against microbial pathogens: communicating current research and technological advances
_______________________________________________________________________________
A. Méndez-Vilas (Ed.)
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 yellowbrown 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 multipletarget 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 sesquiterpenehydroquinones, 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 sesquiterpenoidhydroquinones 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 8,10,18trihydroxy-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
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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 pumpmediated 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 spongeassociated 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 crossresistance 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 antimycobacterial 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
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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, Osulphated 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 4methylaaptamine 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 isonitrilecontaining 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 antimycobacterial 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
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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 structureantimicrobial 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 marinederived 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/mlketoconazole [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 9methyl-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 QuanZhou 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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