Science against microbial pathogens: communicating current research and technological advances
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A. Méndez-Vilas (Ed.)
Antimicrobial activities of microalgae: an invited review
Helena M. Amaro1, A. Catarina Guedes1, F. Xavier Malcata1,2*
1
CIMAR/CIIMAR – Centro Interdisciplinar de Investigação Marinha e Ambiental, Rua dos Bragas nº 289, P-4050-123
Porto, Portugal
2
ISMAI – Instituto Superior da Maia, Avenida Carlos Oliveira Campos, Castelo da Maia, P-4475-690 Avioso S. Pedro,
Portugal
*
Corresponding author
Microalgae exhibit a huge genetic diversity; they may indeed appear as individual cells, colonies or extended filaments.
Ubiquitously distributed throughout the biosphere, they can grow essentially under all types of environmental conditions.
Microalgae are thus some of the most promising stakeholders in blue biotechnology: besides their notable metabolic
versatility, they require only low cost inorganic N- and P-sources, sequester CO2 as base nutrient, and rely on sunlight to
fulfill energy requirements. They are known as well for their richness in bioactive compounds, with promising applications
in pharmaceutical formulations; some are rather active against unwanted bacteria found in aquaculture and food
processing, whereas others exhibit antiviral, antifungal and antialgal features. Their cell-free extracts have accordingly
been tested as additives for food and feed formulation, in attempts to circumvent use of antimicrobial compounds of
synthetic origin, or subtherapeutical doses of regular antibiotics. Recall, in this regard, the growing resistance of some
bacterial strains, owing to the widespread and almost unrestricted use of antibiotics in cattle handling and by consumers at
large. This chapter tackles all such items; for methodological reasons, it is divided into five sections: (1) introduction; (2)
antibacterial action; (3) antiviral action; (4) antifungal action; and (5) antimicroalgal action.
Keywords: antibacterial, antifungal, antiviral, antimicroalgal
1. Introduction
Microalgae exhibit a notable biodiversity; they can in fact be found as individual cells, colonies or extended filaments.
These microorganisms account for the basis of the food chain in aquatic ecosystems; they posses the intrinsic ability to
take up H2O and CO2 that, with the aid of solar energy, are used to synthesize complex organic compounds, which are
subsequently accumulated and/or secreted as primary or secondary metabolites. They are ubiquitously distributed
throughout the biosphere, where they have adapted to survival under a large spectrum of environmental stresses – e.g.
heat, cold, drought, salinity, photo-oxidation, anaerobiosis, osmotic pressure and UV exposure [1]; hence, they may
grow essentially under all environmental conditions available, ranging from freshwater to extreme salinity, and can
survive in moist, black earth and even desert sands – and they have as well been found in clouds, being in addition
essential components of coral reefs. This wide span of ecosystems contributes to the myriad of chemical compounds
that they are able to synthesize, thus accounting for their unique potential as stakeholders in blue biotechnology.
Almost 18,500 new compounds have been isolated from marine sources between 1965 and 2006, yet one estimates
that ca. 97% of all existing marine compounds have not yet been obtained nor characterized [2]. Therefore, microalgae
(especially those from marine origin) represent a unique opportunity to discover novel metabolites, or to produce known
metabolites at lower costs. The rate of rediscovery – i.e. finding metabolites which were already obtained from other
biological sources, is expected to be far lower (i.e. <5%) in microalgae than in more conventional microorganisms (i.e.
> 90%) [3]. Microalgae possess the extra advantage of a substantial metabolic plasticity, dependent on their
physiological state (i.e. stressed vs. nonstressed); likewise, their secondary metabolism can easily be triggered by most
forms of externally applied stress (e.g. lack of a nitrogen source) [4].
Microalgae have for long been used with therapeutic purposes; their systematic screening for biologically active
principles began in the 1950s. However, in the last decade microalgae have become the focus of extensive research
efforts, aimed at finding novel compounds that might lead to therapeutically useful agents [5-7]. Microalgae have
meanwhile been found to produce antibiotics: a large number of microalgal extracts and/or extracellular products have
proven antibacterial, antifungal, antiprotozoal and antiplasmodial [8-11].
The antimicrobial activity of microalgae has been attributed to compounds belonging to several chemical classes –
including indoles, terpenes, acetogenins, phenols, fatty acids and volatile halogenated hydrocarbons [6,7]; for instance,
the antimicrobial activity of supercritical extracts obtained from the microalga Chaetoceros muelleri were related to its
lipid composition [12]. However, the antimicrobial activity detected in several pressurized extracts from Dunaliella
salina may be explained not only by several fatty acids, but also by such compounds as - and -ionone, -cyclocitral,
neophytadiene and phytol [10]. Efforts to identify the compounds directly responsible for those antimicrobial features –
e.g. chlorellin [13], have been on the run, but are still relatively incipient owing the some new classes of compounds
found.
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A. Méndez-Vilas (Ed.)
Microalgal cell-free extracts are already being tested as additives for food and feed formulation, in attempts to
replace antimicrobial compounds of synthetic origin currently in use – including subtherapeutical doses of antibiotics
employed as prophilatic measure in animal breeding [14]. Recall, in this regard, the growing resistance of some
bacterial strains arising from the widespread and essentially unrestricted use of antibiotics in cattle handling, and by
domestic consumers use via self-prescription [15,16]. However, a key factor for their eventual economic feasibility is
the possibility of operating large photobioreactors under aseptic conditions, which are able to produce biomass and
metabolites to sufficiently high levels [17,18].
2. Antibacterial action
The past decade has witnessed a significant increase in the resistance of pathogenic bacteria to antibacterial agents –
with direct implications in human morbidity and mortality. Hence, attention has been paid to a more detailed
understanding of the mechanisms underlying antimicrobial resistance – as well as to improved methods to detect
resistance, new antimicrobial options for treatment of infections caused by resistant microorganisms, and methods to
prevent emergence and spreading of resistance in the first place. Most efforts were devoted to the study of antibiotic
resistance in bacteria for several reasons: (i) bacterial infections are responsible for most community-acquired and
nosocomial infections; (ii) the large and expanding number of antibacterial classes offers a more diverse range of
resistance mechanisms; and (iii) the ability to move bacterial resistance determinants into standard, well-characterized
bacterial strains facilitates more detailed studies of the underlying molecular mechanisms [19].
Pratt et al. [20] isolated the first antibacterial compound from a microalga, Chlorella; a mixture of fatty acids, viz.
chlorellin, was found to be responsible for that inhibitory activity against both Gram+ and Gram- bacteria. Research
aimed at identifying antibacterial active principles produced by microalgae has meanwhile boomed [11]. This
realisation arose e.g. from the risk associated with several multidrug-resistant Staphylococcus aureus (MRSA) strains,
which have been causing an increased concern in healthcare institutions worldwide – since they are not susceptible to
most conventional antibiotics. Hence, discovery of novel antibacterial compounds following distinct biochemical
mechanisms of action is urged. Although microalgae can synthesize a few useful products, search for novel antibiotics
is still incipient; illustrative examples are tabulated in Table 1.
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Table 1 Antibacterial features of selected compounds from microalgae.
Microalga
Phaeodactylum tricornutum
Active compound
Target microorganism
Reference
Eicosapentaenoic acid
MRSA,
Listonella anguillarum,
Lactococcus garvieae,
Vibrio spp.
[21,22]
Short chain fatty acids
-
[23]
Short-chain fatty acids
(butanoic acid and
methyl lactate)
Escherichia coli,
Staphylococcus aureus
[24]
Unsaturated, saturated
long chain fatty acids
Vibrio spp.
[25]
Euglena viridis
Organic extracts
Pseudomonas,
Aeromonas,
Edwardsiella,
Vibrio,
E. coli
[26]
S. costatum
Extra-metabolites
Listeria monocytogenes
[27]
Haematococcus pluvialis
Skeletonema costatum
Staurastrum gracile
Pleurastrum terrestre
[28]
Methanolic extracts
-
Chlorococcum sp.
Aqueous extract
-
[28]
Chlorococcum HS-101
α-Linolenic acid
-
[29]
Chlorokybus atmophyticus
Acetone extract
-
[28]
Dictyosphaerium pulchellum
Klebsormidium crenulatum
Chlamydomonas reinhardtii
Chlorella vulgaris
Methanolic and
hexanolic extracts
S. aureus,
Staphylococcus
epidermidis,
Bacillus subtilis,
E. coli,
Salmonella typhi
[30]
Antibiotics are typically less effective against Gram- bacteria because of their complex, multilayered cell wall
structure – which makes it more difficult for the active compound to penetrate them [31]; this justifies why the
antibacterial activity of the supernatant (and methanolic extracts) is more potent against Gram+ than Gram- bacteria
[11,30].
The activity of cell lysates of P. tricornutum against both Gram+ and Gram- bacteria (including MRSA) – even at
micromole levels, was attributed to eisosapentaenoic acid, a compound synthesized de novo by diatoms [32]; this
polyunsaturated fatty acid is found chiefly as a polar lipid species in structural cell components (e.g. membranes), and
plays a role in microalgal defense – as it is toxic to grazers [33], as well as a precursor of aldehydes with deleterious
effects upon such consumers as copepods [34]. Similarly, hexadecatrienoic acid isolated from P. tricornutum displays
activity against (the Gram+ pathogen) S. aureus. High levels of palmitoleic acid and other bioactive fatty acids were also
found in the fusiform morphotype of P. tricornutum, rather than in the oval morphs of this microalga; that fatty acid is
active against various non-marine, Gram+ human pathogens at micromolar concentrations – and its lethal effects start
immediately upon exposure [22]. Pressurized (liquid) ethanol extracts from Haematococcus pluvialis in its red stage
possess antimicrobial activity against a Gram- bacterium, E. coli, and a Gram+ bacterium, S. aureus; this was once again
associated with the presence of short-chain fatty acids, namely butanoic and methyl lactic acids [24].
The exact mechanism of action of fatty acids remains unknown: they may act upon multiple cellular targets, even
though cell membranes are the most probable ones – as membrane damage will likely lead to cell leakage and reduction
of nutrient uptake, besides inhibiting cellular respiration; conversely, Desbois [21] claimed a peroxidative process.
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Furthermore, compounds synthesized by Scenedesmus costatum, and partially purified from its organic extract,
exhibited activity against aquaculture bacteria because of their fatty acids longer than 10 carbon atoms in chain length –
which apparently induce lysis of bacterial protoplasts. The ability of fatty acids at large to interfere with bacterial
growth and survival has been known for quite some time, but recent structure-function relationship studies suggest that
said ability depends on both their chain length and degree of unsaturation. Such compounds as cholesterol can
antagonize antimicrobial features [12], so both composition and concentration of free lipids should be taken into
account [35].
Among microalgal-derived oxylipins, the antibacterial activities of polyunsaturated aldehydes deserve a special
mention. Such compounds are synthesized by diatoms, e.g. S. costatum and Thalassiosira rotula. One illustrative
example is decadienal – probably derived from (the polyunsaturated) arachidonic acid (C20:4 n-3), which exhibits a
strong activity against such important human pathogens as MRSA and Haemophilus influenza – with MIC values of 7.8
and 1.9 μg/mL, respectively, and well as against E. coli and Pseudomonas aeruginosa, and S. aureus and
Staphylococcus epidermidis (Gram- and Gram+ bacteria, respectively). Furthermore, it impairs growth of diverse marine
bacteria, such as (the Gram-) Aeromonas hydrophila, L. anguillarum, Alteromonas haloplankti, Photobacterium
phosphoreum and Psychrobacter immobilis, and the (Gram+) Planococcus citreus and Micrococcus luteus [22].
3. Antiviral action
A number of infectious diseases caused by viruses have emerged (and re-emerged) in recent years. Although several
antiviral drugs have been specifically developed, drug-resistant mutations are constantly occuring – so new antiviral
active principles are necessary, especially those from sources that do not constitute (or are exposed to) viral pools. This
is why microalgae have received a strong attention as potential suppliers of antiviral agents [36]; a few selected
examples are listed in Table 2.
Table 2 Antiviral features of selected compounds from microalgae.
Microalga
Active compound
Mechanism of action
Navicula directa
Polysaccharide
Inhibition of hyaluronidase
p-KG03
exopolysaccharide
Pheophorbide -,
-like compounds
Inhibition (or slowing down)
of cytopathic effect
HSV1 & 2,
Influenza A virus
Encephalomyocarditis
virus
Inhibition of cytopathic effect
HSV1
[39]
VHSV, ASFV
[40]
Enterovirus 71
[41]
Influenza virus A & B,
RSV A & B,
HSV-1
[42]
Gyrodinium impudicum
Dunaliella primolecta
Chlorella autotrophica
Ellipsoidon sp.
Sulfated
polysaccharides
Cryptomonads
Allophycocyanin
Cochlodinium polykrikoide
Extracellular
sulfated polysaccharides
Replication inhibition
C. autotrophica: 47.4-67.4 %
Ellipsoidon sp.: up to 44 %
Inhibition of cytopathic effect,
delay in synthesis of viral
RNA
Inhibition of cytopathic effect
Target virus
Reference
[37]
[38]
Viral growth is generally divided into three stages, and antiviral action may take place at a single or more stages:
Stage I, which consists on adsorption and invasion of cells; Stage II, or eclipse phase, during which the cell is forced to
synthesize multiple copies of said virus; and Stage III, or maturity and release of virus particles. For instance, the antiHSV activity of the antiviral compound acyclovir® is expressed at stage II, but the anti-HSV factor from Dunaliella sp.
inactivates the viral function at stage I [43,44]. Sulphated exopolysaccharides from marine microalgae have been
claimed to interfere with Stage I of some enveloped viruses [45]; they offer competitive advantages because of their
broad antiviral spectrum against e.g. HSV and HIV-1 [46]. Apparently, their inhibitory effect arises from interaction
with the positive charges on the virus or on the cell surface – which prevents penetration of the former into the host
cells [47,48]; they may also selectively inhibit reverse transcriptase in the case of HIV, thus hampering production of
new viral particles after infection [49] – yet the exact step during viral replication when they act remains to be
elucidated. Antiviral highly sulfated polysaccharides from several species of red microalgae consist mainly of xylose,
glucose and galactose [49,50]; they are unusually stable when exposed to extreme pH and temperature [51].
Another important antiviral action associated with sulfated polysaccharides is against two enveloped rhabdoviruses
bearing significant economic importance: the viral hemorrhagic septicemia virus (VHSV) of salmonid fish and the
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African swine fever virus (ASFV) – see Table 2. Extracts from marine microalgae can find a prophylactic usefulness in
hatcheries against VHSV, and perhaps also against other fish-contaminating enveloped viruses in addition to
mammalian viral diseases [40]. Consequently, application of such compounds appears to be a particularly attractive
option in anti-viral therapy, because their pleiotrophic mode of action is less likely to lead to development of resistant
mutants than other compounds that exhibit only one target throughout the viral life cycle. NMR and MS analyses of the
antiviral compounds synthesized by D. primolecta [39] revealed structures not yet found in nature; in particular, the
pheophorbide-like substances found had the proton at position 21 replaced by a hydroxyl group, which might be the key
for the observed unique antiviral activity.
A homopolysaccharide of galactose with uronic acid (3.0 %, w/w) and sulfate groups (10.3 %, w/w) from
Gyrodinium impudicum strain KG03 [38] exhibited an impressive activity in vitro (EC50=26.9 µg/mL) against swine
encephalomyocarditis virus, which is widespread at the subclinical level; its acute form leads to sudden death in piglets,
as well as reproductive failure in adult animals [52].
Despite their successful antiviral performance, the metabolic pathways leading to sulfated polysaccharides are still
poorly known. Their secretion by unicellular red algae was originally characterized via radiolabeling – which showed
biosynthesis of the carbon chain, and sulfation of the resulting polysaccharide to occur in the Golgi apparatus [53];
these findings were confirmed in Porphyridium sp. [54] and other red microalgae [55]. More recently, Keidan et al. [56]
used 14C pulse-chase experiments and ultrastructural microscopy to conclude that brefeldin A – a membrane-traffic
inhibitor of the Golgi apparatus, decreases the contents of the bound and the soluble forms of polysaccharides, while
inhibiting cell-wall binding of polysaccharides to a greater extent than its soluble counterpart (in both actively growing
and resting cells).
Discovery of small molecules that can specifically disrupt a particular protein-protein interface remains a challenge –
but is of a particular interest in virology, since the antiviral drugs currently available target only viral proteins.
4. Antifungal action
The study of resistance to antifungal agents has lagged for behind that of antibacterial resistance – likely because fungi
were not recognized as important pathogens until several years ago [57,58]. For instance, the annual death rate caused
by candidiasis remained steady between 1950 and 1970, but increased significantly ever since in association with several
changes in medical practice – including more widespread use of therapies that depress the immune system, frequent and
often indiscriminate use of broad-spectrum antibacterial agents, common use of indwelling intravenous devices, and
advent of chronic immunosuppressive viral infections (e.g. AIDS). The associated increase in fungal infections
prompted search for newer and safer agents to combat fungal infections [19] – and a few noteworthy results
encompassing microalgae are listed in Table 3.
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Table 3 Antifungal features of selected compounds from microalgae.
Microalga source
Active compound
Target microorganism
Chlamydomonas reinhardtii
Chlorella vulgaris
Reference
Candida kefir,
Aspergillus niger,
Aspergillus fumigatus
[30]
A. niger,
Trichomonas foetus
[59]
Methanolic extracts
Oocystis sp.
Scenedesmus obliquus
Amphidinium sp.
Karatungiols
Goniodoma pseudogoniaulax
Goniodomin A
-
[28,60]
Gambierdiscus toxicus
Polyether compounds
(gambieric acids A and B)
-
[28,61]
-
[28]
-
[28]
Prorocentrum lima
Dinophysis fortii
Haematococcus pluvialis
Polyether compounds
Butanoic acid and methyl
lactate
Chlorella pyrenoidosa,
Scenedesmus quadricauda
-
Candida albicans
[24]
A. niger,
Aspergillus flavus,
Penicillium herquei,
Fusarium moniliforme,
Helminthosporium sp.,
Alternaria brassicae,
Saccharomyces cerevisiae,
C. albicans
[62]
Katircioglu et al. [63] studied 10 microalgal strains, previously isolated from distinct freshwater reservoirs in Turkey,
for their antifungal performance upon three yeasts (S. cerevisiae, C. albicans and Candida tropicalis); Oscillatoria sp.
and Chlorococcus sp. were found to perform best.
Pressurized liquid ethanol extracts of H. pluvialis were tested by Santoyo et al. [24] against C. albicans and A. niger;
all extracts were active against the former, but not against A. niger. The main compounds responsible for such
antifungal activity were claimed to be butanoic acid and methyl lactate, both of which had previously been described to
possess antimicrobial activity [64,65].
Abedin and Taha [62], on the other hand, studied the antifungal activity of two green microalgae (C. pyrenoidosa and
S. quadricauda) against 8 fungi (A. niger, A. flavus, P. herquei, F. moniliforme, Helminthosporium sp., A. brassicae, S.
cerevisiae and C. albicans) – with favourable results for nearly all extracts; these data are consistent with those by Volk
and Furkert [66], who found microalgae to exhibit a high biological activity against P. aeruginosa, C. tropicalis and S.
cerevisiae.
The supernatant (methanolic and hexane) extracts of several microalgae against four strains of fungi (C. kefyr, C.
albicans, A. niger and A. fumigatus) were tested by Ghasemi et al. [30]; nine Chlorella vulgaris spp., Chlamydomonas
reinhardtii, Oocystis sp. and S. obliquus proved active against C. kefyr, A. niger and A. fumigatus, but only marginally
active against C. albicans; their results indicated that an antifungal activity was predominantly associated with
Chlorella spp. Furthermore, several solvents were tested, but only methanolic extracts were found to possess a feasible
antifungal activity.
5. Antimicroalgal action
Inhibitory phenomena between microalgal cells have been reported in the past; Bagchi et al. [67] originally proposed
that natural algaecides could effectively be applied in control of toxic algal blooms. However, Pratt [68] was the first to
report that growth of C. vulgaris was depressed by a compound (chlorellin) that was produced and excreted into the
medium – and several other extracellular metabolites able to inhibit their own growth and the growth of other species
have meanwhile been reported [69]; some examples are listed in Table 4.
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Table 4 Antimicroalgal features of selected compounds from microalgae.
Microalga source
Active compound
Target microorganism
Reference
Peridinium bipes
Water-soluble extract
[28,70]
Isochrysis galbana
C22H38O7 from cell-free
filtrates
Microcystis aeruginosa
Dunaliella salina,
Platymonas elliptica,
C. vulgaris,
Chaetoceros muelleri,
Chlorella gracilis,
Nitzschia closterium,
P. tricornutum
Nitzschia frustulum
Scrippesiella trochoidea
Prorocentrum donghaiense
-
[71]
-
Autoinhibition was also observed in H. pluvialis and S. costatum [72,73]. The antimicroalgal ability appears to derive
either from interference with chlorophyll and protein syntheses [71] – as in the case of I. galbana, or because of
changes in membrane permeability coupled with dissociation of phycobilin assemblages in the thylakoid membranes –
thus leading to leakage across the cell wall [70].
Acknowledgements A PhD fellowship (ref. SFRH/BD/62121/2009), supervised by author F.X.M., was granted to author H.M.A.,
under the auspices of ESF (III Quadro Comunitário de Apoio) and the Portuguese State. A postdoctoral fellowship (ref.
SFRH/BPD/72777/2010), supervised by author F.X.M., was granted to author A.C.G., also under the auspices of ESF (III Quadro
Comunitário de Apoio) and the Portuguese State.
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