Antifungal and Anticancer Activity of Amphidinium spp.: Comparison
Please note this is a comparison between Version 1 by Angela Sardo and Version 2 by Jason Zhu.

Dinoflagellates make up the second largest marine group of marine unicellular eukaryotes in the world ocean and comprise both heterotrophic and autotrophic species, encompassing a wide genetic and chemical diversity. They produce a plethora of secondary metabolites that can be toxic to other species and are mainly used against predators and competing species. Dinoflagellates are indeed often responsible for harmful algal bloom, where their toxic secondary metabolites can accumulate along the food chain, leading to significant damages to the ecosystem and human health. Secondary metabolites from dinoflagellates have been widely investigated for potential biomedical applications and have revealed multiple antimicrobial, antifungal, and anticancer properties. Species from the genus Amphidinium seem to be particularly interesting for the production of medically relevant compounds. The present review aims at summarising current knowledge on the diversity and the pharmaceutical properties of secondary metabolites from the genus Amphidinium. Specifically, Amphidinium spp. produce a range of polyketides possessing cytotoxic activities such as amphidinolides, caribenolides, amphidinins, and amphidinols. 

  • Amphidinium
  • dinoflagellates
  • biological activity

1. Introduction

Dinoflagellates are a group of microalgae widely distributed in freshwater and marine environments, which comprise autotrophic, heterotrophic, and mixotrophic species. A number of dinoflagellate species have been described as symbionts (e.g., Symbiodinium, Pelagodinium), parasites (e.g., Amoebophrya, Ichthyodinium), and grazers (e.g., Gyrodinium) [1][2][3][4][5][6][7]. The number of species belonging to this taxon has been recently estimated at ca. 6000 species; among them, more than 60% are living and the remaining part represent fossil species [8]. The variety of feeding behaviours is comparable to their biochemical diversity, that leads to the production of a plethora of secondary metabolites, most of them possessing significant biological activities towards cancer cell lines, bacteria, viruses, fungi, larvae, and other algae [9][10][11][12][13][14][15][16]. Among them, some toxic molecules (saxitoxin, tetrodotoxin, okadaic acid) have been largely investigated to assess their potential in the pharmaceutical field since the 2000s [17]. However, toxins can be detrimental for human health, especially when massively released in the water column during harmful algal blooms (HABs). HAB frequency has been constantly increasing over the last few decades because of climate change and coastal eutrophication [18][19][20]. Among the huge species richness of dinoflagellates, the genus Amphidinium seems to be particularly relevant for its high potential in producing bioactive metabolites. Species belonging to this genus, along with other closely related genera, produce several poliketides, including amphidinols, amphidinolids, amphidinins, and iriomoteolides, and lots of these secondary metabolites possess significant cytotoxic activity, which is described in the present article. With respect to other dinoflagellates, usually characterised by low growth rates [21], Amphidinium spp. are able to perform rapid growth, and reach high abundances and relatively high biomass yields under appropriate culturing conditions [22][23]. This could be advantageous in a perspective of a large-scale production of metabolites potentially marketable in the industrial sector. Moreover, modulation of culture conditions, such as light intensity and nutrient supply, can further promote the production of specific metabolites [24].
Antimicrobial resistance developed by some pathogens is a serious public health issue that needs to be resolved through the common efforts of the scientific community, society, and policy makers. An increasing number of infectious diseases caused by different pathogens, such as bacteria, parasites, viruses, and fungi, are difficult to prevent and to treat because of adaptation mechanisms evolved by several distinct pathogens to overcome the action of several commonly used drugs. Antimicrobial resistance has been reported to cause ca. 700,000 fatalities per year worldwide [25]. In particular, bacterial resistance to antibiotics seems to be the microbe-driven drug adaptation strategy leading to the most serious issues for human health; indeed, several bacterial species exhibit antibiotic resistance, and bacterial infections can often lead to severe consequences [26]. Bacteria exhibiting the most dangerous drug adaptation patterns are multidrug-resistant strains affiliated to the species Staphylococcus aureus, Escherichia coli, Enterococcus faecium, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa [27]. Innovative and high-quality antibacterial compounds are thus urgently required to replace the antibiotics that are going to be rendered increasingly ineffective by drug resistance [28]. Since most of the antibiotics known to date have been developed from natural products, the marine environment can represent a promising source, still little explored, of new bioactive compounds with antibacterial activity. Although the dinoflagellate Amphidinium produces a plethora of secondary metabolites with numerous bioactive properties, few studies have investigated the potential of Amphidinium spp. as a source of antibacterial molecules. The first evidence was reported by Kubota and co-authors [29], in which the amphidinolide Q, a cytotoxic 12-membered macrolide, and four new 4,5-seco-analogues, namely amphidinins C, D, E, and F, were identified in the liquid medium in which Amphidinium sp. strain 2012-7-4A was cultured. This strain was isolated from the marine flatworm Amphiscolops sp. collected at Ishigaki, Okinawa, Japan. The antibacterial activity was evaluated against two Gram-positive bacteria, S. aureus and Bacillus subtilis, and a Gram-negative bacterium, E. coli. Results demonstrated that amphidinins C and E and amphidinolide Q were active against S. aureus and B. subtilis, while only amphidinolide Q was effective against E. coli (minimum inhibitory concentration—MIC—of 32 µg/mL for all trials except B. subtilis treated with amphidinolide Q, MIC of 16 µg/mL. Amphidinins D and F and the glycosides-related compounds did not show antibacterial activity. More recently, Barone and co-authors [30] evaluated the antibacterial activity of Amphidinium carterae strain LACW11, isolated on the west Irish coast, against two Gram-positive bacteria, S. aureus and E. faecalis. The activity was detected mainly in three fractions obtained by ethyl acetate extraction and C18 fractionation with increasing percentages of methanol, namely fractions J (80% methanol), I (90% methanol), and K (100% methanol), with an MIC ranging from 16 µg/mL to 64 µg/mL for S. aureus and from 64 µg/mL to 256 µg/mL for E. faecalis. The chemical identification of these fractions, through a metabolomic approach, highlighted the presence of amphidinol AM-A and a new derivative, dehydroAM-A, in fractions I and J, respectively. These two compounds were mostly responsible for the antibacterial activity against S. aureus. Fraction K, which showed bioactivity against E. faecalis, did not contain known amphidinols, suggesting the presence of other bioactive molecules in this fraction. Antimicrobial activity occurs throughout nature; there are many examples of bioactive secondary metabolites produced by a variety of both land-based and underwater sources [31]. Terrestrial and marine secondary metabolites have different structural features and bioactive proprieties, probably due to the different environmental characteristics in which the original organisms occur [32]. Chassagne and co-authors [33] reported a systematic analysis of scientific data about plants possessing significant antibacterial activities, selecting data on 958 species derived from 483 scientific articles. This analysis indicated the crude extracts of the plant species Sambucus nigra L. (Adoxaceae), Echinops kebericho Mesfin (Asteraceae), Mikania glomerata Spreng. (Asteraceae), Curcuma longa L. (Zingiberaceae), and Combretum album Pers., (Combretaceae) as those with the most potent antibacterial activity, with MIC values ranging from 3.5–16 μg/mL, comparable or slightly lower compared to MIC of Amphidinium-related compounds. Essential oils are concentrated hydrophobic liquids extracted from plants; they are generally very complex in terms of chemical composition, showing a powerful antibacterial activity, with MIC values that reached 0.09 μg/mL for the plant Hibiscus surattensis L. (Malvaceae), probably due to the synergistic effect between the different compounds present in the extracts. In addition to antibacterial activities, the species A. carterae has been also investigated for its antialgal and antilarval activity, as reported by Kong and co-authors [9]. These properties were tested to find environmentally friendly antifouling compounds for marine industries. A series of unsaturated and saturated 16- to 22-carbon fatty acids, including hexadecanoic acid, octadecanoic acid, 9-octadecenoic acid, octadecatetraenoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid, exhibited antialgal activity against the diatom Skeletonema costatum, as indicated by changes in the chlorophyll a fluorescence intensity of the microalgal suspension, and antilarval activity against Amphibalanus amphitrite larvae with relatively low lethal concentrations. The antimicrobial properties of fatty acids isolated from marine organisms are well documented [34]. The type and potency of bioactivity depends on the chemical structure, in terms of degree of saturation, length of carbon chain, and the orientation of the double bonds [35]. Among the most promising fatty acids, EPA showed potent activity against different bacteria [36], and palmitic acid revealed antialgal activity and antifouling properties against the diatom Cylindrotheca closterium with a half-maximal effective concentration (EC50) value of 45.5 μg/mL [37].

2. Antifungal Activity

Fungal infections represent a serious clinical problem, especially for immunocompromised and seriously ill patients. Among clinical infections, those caused by the species Aspergillus niger and Candida albicans can cause morbidity and mortality when associated with other diseases, advanced age, and/or patients who have undergone an organ transplant [38]. Dinoflagellates include a high proportion (ca. 70%) of species possessing biocide activity against fungal infections [39], and most of them were tested on the abovementioned fungi [12][40][41]. Some potent dinoflagellate-derived compounds with antifungal activity were isolated over 30 years ago from the species Gamberdiscus toxicus [42], identified as polyether compounds termed as gambieric acids [43]. However, most of the antifungal compounds derive from the genus Amphidinium. In less recent works (from the late 1990s to the first decade of the 2000s), the biological activity of Amphidinium compounds was evaluated by susceptibility tests based on paper disks impregnated of specific concentrations of the agent, which were aimed at identifying the minimum effective concentration (MEC) able to inhibit fungal proliferation [44][45]. More precise in vitro assays were performed to detect the MIC of the antifungal agents during the last decade. MIC can be assessed by colorimetric assays based on the reduction of resazurin, a nonfluorescent blue dye that is reduced to the pink-coloured resorufin [46], or by the broth microdilution method [47], which is based on the inoculation of a standardised number of organisms in a liquid medium exposed to serial dilutions of an antifungal agent [12]. MIC values of Amphidinium-derived compounds are comparable or slightly higher than organic extracts obtained from natural compounds of plant origin, such as Abutilon theophrasti, Acacia nilotica, Cinnamomum verum and Ficus polita, while they are—as expected—lower than plant-derived essential oils [48]. Amphidinols can be also considered equally or more effective than other antifungal compounds isolated from some marine organisms [49], such as the bacterium Acinetobacter sp., which produces indolepyrazines exhibiting a MIC of 12–14 µg/mL against C. albicans [50], and the fungus Penicillum sp., which contains andrastone C and andrastone B exhibiting MIC values against C. albicans of 6 and 13 μg/mL, respectively [51]. The antifungal effects exhibited by compounds from Amphidinium spp. and other marine organisms towards aspergillosis is comparable (MIC values have the same order of magnitude) to plant-derived solvent extracts from the families Asteraceae and Lamiaceae, but generally produce a more marked effect of flavonoids and phenolic compounds extracted from other several species (families: Fabaceae, Aizoaceae, Anacardiaceae, Hypericaceae, Cornaceae, Bignoniaceae, Aquifoliaceae) that possess MIC values of 0.01–6.25 mg/mL [52]. Antifungal activity of Amphidinol A, C, and 18 against C. albicans can be considered also comparable to that of fluconazole, one of the most common synthetic compounds that is actually considered as one of the mainstays for the treatment of Candida-derived infections. Indeed, MIC values of these compounds are inside or below the range of the susceptible dose-dependent (SDD, MIC: 16–32 µg/mL) clinical breakpoint for fluconazole and Candida, and below the resistant (R; MIC ≥ 64 µg/mL) breakpoint [53]. Few data regarding Amphidinium-derived molecules with antifungal activity are available in the literature with respect to those of synthetic compounds (e.g., triazoles), and the application of different methodologies can make the direct comparison among these natural compounds with the most common antifungal agents difficult. Moreover, the increasing resistance exhibited by Candida and Aspergillus species towards the most common biocides [54][55][56] have already highlighted the need to test and validate the efficiency of novel azoles with improved spectra of activity [57].

3. Anticancer Activity

In addition to antimicrobial and antifungal activities, the genus Amphidinium has been widely investigated for the anticancer properties of its secondary metabolites. Both symbiotic and free-living Amphidinium spp. have been reported to possess several anticancer compounds. An extensive review on the anticancer properties of macrolides and polyketides produced by Amphidinium spp. is provided by Kobayashi and Tsuda [58]. Overall, these authors classified all the amphidinolides isolated and identified back in 2006, and reported the presence of 34 cytotoxic amphidinolides in 7 Amphidinium sp. strains. The first bioactive compounds were isolated from an Amphidinium sp. symbiont of the flatworm Amphiscolops breviviridis and named amphidinolides B, G, and H [59]. In particular, amphidinolides G and H have proven to be very effective against murine leukemia cells. Amphidinolide B, Amphidinolide H, and amphidinolide H3 revealed instead cytotoxic activity against murine leukemia and human epidermoid carcinoma. Amphidinol-22 was isolated from crude extracts of A. carterae and was found to exhibit moderate cytotoxic activity against lung, liver, and pancreas cancer cell lines [60]. The amphidinolides most effective against cancer cells are Amphidinolide N, which was found to exhibit potent cytotoxic activity against human cervix adenocarcinoma cells—half maximal inhibitory concentration (IC50) = 0.01 ng/mL—and Amphidinolides B and H, which were revealed to be effective against murine leukemia (IC50 = 0.14 and 0.48 ng/mL, respectively). In addition to amphidinolides, Amphidinium spp. possess other long-chain compounds such as luteophanols, colopsinols, and caribenolide, the latter possessing cytotoxic properties [61]. The most potent anticancer compounds identified to date are two macrolides (isocaribenolide-I and chlorohydrin-2) recently isolated from a free-living Amphidinium sp. (strain KCA09053) and found to possess high cytotoxic activity against human cervix adenocarcinoma cells [62]. Caribenolide I, isolated from a free-living Amphidinium sp., was found to possess cytotoxic activities towards human colon tumour cells [63]. Tsuda et al. [64] identified amphidinolide U while Kobayashi et al. [65] isolated amphidinolides T2, T3, and T4, from a symbiotic Amphidinium sp.. These amphidinolides exhibit moderate cytotoxic activity (IC50 = 7–12 μg/mL) against murine leukemia (L1210) [64][65]. Since the concentration of amphidinolides can be, in most cases, extremely low within Amphidinium spp. cells, several authors synthesised amphidinolides in the laboratory; for example, Lu et al. [66] synthesised amphidinolide B2 and demonstrated its activity against human solid (IC50 = 1.6 ng/mL) and blood tumour cells (53.9 ng/mL). Furstner et al. [67] published a protocol for the synthesis of the most effective amphidinolides: Amphidinolides B, D, G, and H. In addition, very potent anticancer molecules (IC50 = 68 ng/mL against melanoma cell lines A2058) similar to amphidinols have been recently isolated from the Octocoral Stragulum bicolor [68]. Overall, on the one hand laboratory synthesis of amphidinolides allows for the selection of specific compounds and the implementation of a single synthetic process, leading to amphidinolides at a higher degree of purity, on the other hand mass culturing Amphidinium spp. under the appropriate physical and chemical conditions may lead to the production and the extraction of these amphidinolides without applying complex laboratory protocols. The comparison between these two alternative processes for the production of selected anticancer compounds needs to be evaluated for each specific molecule.


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