Anti-Candidal Marine Natural Products: A Review

Candida spp. are common opportunistic microorganisms in the human body and can cause mucosal, cutaneous, and systemic infections, mainly in individuals with weakened immune systems. Candida albicans is the most isolated and pathogenic species; however, multi-drug-resistant yeasts like Candida auris have recently been found in many different regions of the world. The increasing development of resistance to common antifungals by Candida species limits the therapeutic options. In light of this, the present review attempts to discuss the significance of marine natural products in controlling the proliferation and metabolism of C. albicans and non-albicans species. Natural compounds produced by sponges, algae, sea cucumber, bacteria, fungi, and other marine organisms have been the subject of numerous studies since the 1980s, with the discovery of several products with different chemical frameworks that can inhibit Candida spp., including antifungal drug-resistant strains. Sponges fall under the topmost category when compared to all other organisms investigated. Terpenoids, sterols, and alkaloids from this group exhibit a wide array of inhibitory activity against different Candida species. Especially, hippolide J, a pair of enantiomeric sesterterpenoids isolated from the marine sponge Hippospongia lachne, exhibited strong activity against Candida albicans, Candida parapsilosis, and Candida glabrata. In addition, a comprehensive analysis was performed to unveil the mechanisms of action and synergistic activity of marine products with conventional antifungals. In general, the results of this review show that the majority of chemicals derived from the marine environment are able to control particular functions of microorganisms belonging to the Candida genus, which can provide insights into designing new anti-candidal therapies.


Introduction
Invasive and chronic fungal infections need particular medical attention since they are associated with a significant rise in treatment costs and a high fatality rate [1].Patients who have lengthy hospital stays with compromised immune systems are more likely to get fungal infections.Candida, Aspergillus, and Cryptococcus are the three main genera of fungi that cause human diseases, ranging from superficial to invasive infections [2,3].In contrast to other causes, they account for 90% of fungal infections that collectively afflict more than a billion people worldwide [4,5].The four principal groups of antifungal drugs are polyenes, azoles, echinocandins, and pyrimidine analogues, which have been extensively employed in recent decades [6,7].The therapeutic effectiveness of these antifungals depends on several factors, including host immunological response, fungal isolate origin, antifungal drug characteristics, and the emergence of drug tolerance and drug resistance.Among these factors, drug resistance is the prime concern in the world population since microorganisms can acquire several defense mechanisms against different classes of drugs [8,9].These mechanisms can suppress the action of drugs by reducing the binding affinity with the drug target in fungal cells, leading to the overexpression or mutation in drug targets, the overproduction of hydrolytic enzymes, and alteration in effective drug concentration through the modulation of efflux activity [9,10].
Natural products are chemical molecules produced by several organisms living in different habitats [11,12].There is a high degree of chemical diversity among biological organisms, resulting in unique structural and functional properties.Natural products have crucial roles in cellular processes, and many of them have been correlated with important biological functions [13].The importance of natural products has been extensively reported in research focused on developing novel drugs against life-threatening conditions.The structures of natural products are entirely different from synthetic chemical products; they are more complex and have specific biological properties.The differentiation of natural products from synthetic chemical libraries provides a potential source for the identification of newer chemicals.The identification of natural products has been established since the 19th century and comprises chemical structures from terrestrial and marine environments; however, studies associated with marine natural products are limited compared with those focused on terrestrial sources.
Around 70% of Earth's space is occupied by oceans, enriched with different floral and faunal diversity.To adapt to the harsh environment, marine organisms evolved themselves, thus directly or indirectly incorporating valuable chemical compounds with unique properties.For example, more than 30,000 chemical compounds were reported from the marine environment with anticancer properties [14,15].Nevertheless, the extrapolation of marine compounds from the deep sea is still challenging due to many factors, including high cost, the requirement of highly sensitive instruments, time consumption, and the workforce employed [15].Moreover, the quantity of compounds produced by an organism is relatively small, and chemical synthesis is hampered by its complex structural features.Currently, total synthesis and semi-synthesis are commonly used to overcome the supply-demand challenges of natural products.For this, biotechnological approaches are encouraged to obtain the maximum level of specific compounds using some large-scale fermentation techniques [16,17].
In relation to antifungal action, there are several review publications available about natural compounds from different sources; nonetheless, there are no specific publications on anti-candidal metabolites from marine resources.In light of the aforementioned antifungal resistance concerns, we were prompted to seek detailed information on marine natural products that can be effective against C. albicans and some non-albicans species.We expect that this review, which encompasses more than 150 articles from the previous three decades, can fill the knowledge gap regarding natural products targeting Candida infections.In this review, marine natural products from sponges, algae, sea cucumber, bacteria, fungi, and other organisms are presented and discussed in relation to their specific properties against Candida spp.(Figure 2).(Source: https://www.marinepharmacology.org/, accessed on 10 July 2023).
In relation to antifungal action, there are several review publications available about natural compounds from different sources; nonetheless, there are no specific publications on anti-candidal metabolites from marine resources.In light of the aforementioned antifungal resistance concerns, we were prompted to seek detailed information on marine natural products that can be effective against C. albicans and some non-albicans species.We expect that this review, which encompasses more than 150 articles from the previous three decades, can fill the knowledge gap regarding natural products targeting Candida infections.In this review, marine natural products from sponges, algae, sea cucumber, bacteria, fungi, and other organisms are presented and discussed in relation to their specific properties against Candida spp.(Figure 2).(Source: https://www.marinepharmacology.org/, accessed on 10 July 2023).
In relation to antifungal action, there are several review publications available about natural compounds from different sources; nonetheless, there are no specific publications on anti-candidal metabolites from marine resources.In light of the aforementioned antifungal resistance concerns, we were prompted to seek detailed information on marine natural products that can be effective against C. albicans and some non-albicans species.We expect that this review, which encompasses more than 150 articles from the previous three decades, can fill the knowledge gap regarding natural products targeting Candida infections.In this review, marine natural products from sponges, algae, sea cucumber, bacteria, fungi, and other organisms are presented and discussed in relation to their specific properties against Candida spp.(Figure 2).

Sponges
A notable benthic community that may be found in many habitats of fresh and marine water is the sponge [24].The generation of bioactive compounds by sponges has been closely linked to the enrichment of the sponge community with distinct populations of bacteria.Like other filter feeders, sponges never move about their surroundings in search of food and cannot flee from predators.Meanwhile, all sponge species continually produce specific substances as a defense strategy against their predators, including fish, turtles, and invertebrates [25,26].The biological activities of these substances have been explored, and many of them showed activity against Candida spp., which are presented in Figure 3 and Table 1 and discussed below.
of food and cannot flee from predators.Meanwhile, all sponge species continually produce specific substances as a defense strategy against their predators, including fish, turtles, and invertebrates [25,26].The biological activities of these substances have been explored, and many of them showed activity against Candida spp., which are presented in Figure 3 and Table 1 and discussed below.

Glycoside Derivatives
Among glycoside derivatives, two compounds from the marine sponge Oceanapia sp. have been investigated: oceanalin A (C38) and B (C2).These compounds are sphingoid tetrahydoisoquinoline β-glycosides unexpectedly discovered in the organic extract from this sponge.Previous studies proved their in vitro antifungal action against C. glabrata, in which oceanalin A (C38) showed a minimum inhibitory concentration (MIC) of 30 µg/mL [43], and oceanalin B (C2) exhibited a MIC of 25 µg/mL [28].Oceanapiside (C1), another compound purified from the methanol extract of the sponge Oceanapia phillipensis, also showed activity against C. glabrata.This compound was tested on a fluconazole-resistant strain, and its mechanism of action was associated with a disturbance in the sphingolipid pathway [27].However, oceanapiside (C1) was not active against C. albicans and C. krusei strains [54].
In addition, tetramic acid glycoside compounds, called aurantosides, have been studied as potential antifungal agents.Aurantosides D (C46), E (C47), and F (C48) were isolated from the marine sponge Siliquariaspongia japonica.Among them, only aurantosides D (C46) and E (C47) were found to be active against C. albicans, with inhibition zones of 9.5 and 9.7 mm and MICs of 11 and 13.6 µg/mL, respectively [47].Aurantoside K (C23) was isolated from the Fijian marine sponge Melophlus and showed a wide spectrum of antifungal activity against drug-resistant C. albicans strains, with MICs of 31.25 µg/mL and 1.95 µg/mL [39].Aurantoside J (C32), another tetramic acid glycoside isolated from an Indonesian specimen of Theonella swinhoei, was found to be active against all the Candida strains tested (MIC >16 µg/mL), including C. albicans, C. parapsilosis, C. glabrata, and C. tropicalis [41].

Alkaloids
Several alkaloid compounds from marine sponges with anti-candidal activity were reported, such as hemimycalins, nakamurines, agelasines, nagelamides, zamamidine, and ceratinadins.Hemimycalins A (C13) and B (C14) are newly discovered hydantoin alkaloids from Hemimycale arabica, a marine sponge found in the Red Sea.Both of these alkaloids showed activity against Escherichia coli and C. albicans at 100 µg/disc, resulting in inhibition zones of 10-20 mm [33].
Other groups of marine sponges produce a specialized type of chemical substance known as manzamine alkaloids, which have several important biological activities.For example, zamamidine D (C9), derived from the marine sponge Amphimedon sp., showed antimicrobial activity against various pathogens, including C. albicans, with a MIC of 162 µg/mL [56].In addition, ceratinadins A (C33) and B (C34), derived from the Okinawan sponge Pseudoceratina sp., were active against C. albicans at concentrations of 2 and 4 µg/mL, respectively [42].

Peptides
Most peptide compounds were isolated from the sponge Theonella sp., including theonellamide, cyclolithistide, theonegramide, and microsclerodermin.Amongst these peptides, theonellamide G (C16) is a new bicyclic glycopeptide from Theonella swinhoei that showed potential antifungal activity (MIC of 4.49 and 2.0 µM) against wild and drugresistant strains of C. albicans, as well as high toxicity (6.0 µM) to the HCT-16 human colon adenocarcinoma cell line [35].Similarly, theonellamide F (C54) exhibited antifungal activity against unspecific Candida spp. with MIC values of 3-12 µg/mL, and toxicity to leukemia cells (L1210 and P388) at an IC50 of 3.2 and 2.7 µg/mL [52].Cyclolithistide A (C50), a cyclodepsipeptide, had significant antifungal activity against a reference strain of C. albicans (ATCC 24433), at a concentration of 202 µg/mL [49].Additionally, theonegramide (C53) and microsclerodermin C (C49) also inhibited the growth of C. albicans, as reported by Bewley and Faulkner (1994) and Schmidt and Faulkner (1998), respectively [48,51].Furthermore, there are peptides extracted from other sponges that have been reported to have antifungal activity.Discobahamin A (C56) and B (C57) (bioactive cyclic peptides) were isolated from the alcoholic extract of deep-water marine sponge Discodermia sp., but their antifungal activity against C. albicans was considered weak compared with other marine peptides [57].

Terpenoids
Most bioactive terpenoids known are the group of phorbasins isolated from Phorbas sponges, including diterpenes, tetraterpenes, and sesterterpenes [58].To date, over 11 phorbasins have been isolated and characterized with various biological activities, but only a few have exhibited antifungal activity.Two potent antifungal agents are phorboxazoles A (C51) and B (C52), which are cytostatic macrolides.These compounds have shown potent in vitro antifungal activity against C. albicans and Saccharomyces carlsbergensis at a concentration of 1 µg/disk [50].Another example of a phorbasin with antifungal activity is phorbasin H (C17), which has been shown to prevent the yeast-to-hypha transition of C. albicans [36].
In addition to phorbasins, other terpenoids from marine sources have been identified as potential antifungal agents, such as puupehenone (C60) extracted from Stronglyophora hartmani, a deep-water marine sponge.Promisingly, puupehenone (C60) caused a disturbance in the fungal cell wall integrity pathway, along with Hsp90 function, and enhanced the antifungal activity of echinocandins against drug-resistant C. albicans and C. glabrata [59].

Algae
Currently, there are over a million species of algae already known on Earth.Besides maintaining the CO 2 levels and preventing global warming, algae are important sources of metabolites with nutritional and health benefits.Many of these metabolites present antimicrobial action and are of great interest to the pharmaceutical industry.In addition, the metabolic plasticity of algae facilitates culture development and consequently the production of pharmacological substances at a large scale.It is known that among the red, green, and brown algae, the red algae provide the greatest number of bioactive substances, such as polysaccharides (like alginate and agar), lipids, polyphenols, steroids, glycosides, flavonoids, tannins, alkaloids, and triterpenoids [29].
Indeed, most compounds with anti-candidal activity were extracted from red algae (Table 2), including Q-griffithsin (Q-GRFT) (61), a lectin derived from Griffithsia sp.alga, which exhibited a broad of spectrum antifungal activity against C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. auris [63].In a murine model of vaginal candidiasis, Q-GRFT treatment reduced the fungal burden and enhanced the clearance of the infection without affecting immune cell phenotypes [64].Similarly, callophycin A (C62), a natural product of red alga Callophycus oppositifolius, was found to suppress C. albicans growth and decrease fungal burden in vaginal candidiasis in animal models, with significant reductions in proinflammatory markers [65].On the other hand, 10-hydroxykahukuene B (C63), 9deoxyelatol (C64), isodactyloxene A (C65), and laurenmariallene (C66) from the species of red alga Laurencia mariannensis did not exhibit good anti-candidal activity [66].Compounds extracted from green algae have also been explored for the identification of new antifungal agents.For example, the chemical extraction of the green alga Caulerpa racemosa resulted in two rare para-xylene derivatives caulerprenylols A (C92) and B (C93).In vitro assay revealed that caulerprenylol B (C93) had a broad spectrum of antifungal activity against C. glabrata, Trichophyton rubrum, and Cryptococcus neoformans [72].

Sea Cucumber
Sea cucumbers have great medicinal value in China and other Asian countries, where they have been used as tonic food for thousands of years.Currently, it is known that these animals can produce important natural products with potential antifungal action (Table 3).Among these species, triterpene glycosides are particularly noteworthy.A new sulfated triterpene glycoside, named coloquadranoside A (C94), was obtained from the sea cucumber Colochirus quadrangularis.This compound was effective against C. albicans, C. tropicalis, and C. parapsilosis, with MIC ranges of 4-25, 8-30, and 4-32 µg/mL, respectively.Interestingly, it was also found to be cytotoxic for tumor cell lines and had immunomodulatory activity [79].Non-sulfated triterpene glycosides have also been investigated, including 10 new saponins called coustesides A-J (C99-C108) extracted from Bohadschia cousteaui.These compounds had antifungal action against C. albicans, with their zone of inhibition ranging from 10.7 ± 0.05 to 18.0 ± 0.01 [80].Likewise, other new triterpene glycosides were extracted from Stichopus variegates: variegatusides C-F (C109-C112), variegatusides A (C113), B (C114), and holothurin B (C133).Amongst these compounds, variegatuside D (110) was the most effective against C. albicans, C. pseudotropicalis, and C. parapsilosis, with a MIC of 3.40 µg/mL [81].

Bacteria
Marine bacteria live in an extremely complex environment with huge diversity.The ocean column consists of approximately 10 6 bacterial cells per milliliter of water [87].Due to genomic adaptability to complex environments, they can exert multiple functions and produce several biologically active molecules [88].Thereby, marine bacteria can provide sustainably active pharmacological ingredients without harming biodiversity.For these reasons, marine microbes have been recognized as a source of bioactive compounds, gaining great attention among pharmaceutical researchers.

Actinomycetes
Actinomycetes are Gram-positive filamentous bacteria that are known for their ability to produce a wide range of bioactive compounds, including antifungal metabolites [89].These bacteria are commonly found in soil, but they can also colonize other niches such as water, plants, and animals.The genera that produce the most commercially important biomolecules are Streptomyces, Nocardia, Saccharopolyspora, Amycolatopsis, Micromonospora, and Actinoplanes [90,91].The detailed structure of some important natural products from marine Actinomycetes is presented in Figure 4 and Table 4.Among the aforementioned genera, Streptomyces has gained more attention.The ability of Streptomyces to produce antifungal metabolites is associated with their complex genome, which contains numerous biosynthetic gene clusters that encode the production of a variety of secondary metabolites.The number of secondary metabolites has continuously increased in response to the emergence of tools and bioinformatic resources and the enhancement of deep-sea exploration technology.However, information regarding biosynthetic gene clusters still needs further investigation, such as the use of next-generation sequencing methods to obtain the genetic data of the target organisms [117].The antifungal compounds from Streptomyces are mainly polyenes, macrolides, and peptides, which have potent activity against a broad spectrum of fungal pathogens [118][119][120].Several examples are cited below.

Fungi
The natural products produced by marine fungi can be classified into several groups, including alkaloids, polyketides, terpenoids, peptides, and phenolics, among others.Some of the most interesting natural products from marine fungi include cytotoxic compounds, with potential anticancer activity; immunomodulatory compounds, with potential applications in autoimmune diseases; and antimicrobial compounds, with potential applications in combating drug-resistant pathogens.The discovery of natural products from marine fungi is a rapidly growing field of research, as scientists continue to explore the vast and largely unexplored marine environment.The potential of these natural products to serve as lead compounds for drug discovery has generated significant interest, with several marinederived compounds already in clinical trials.In addition, the sustainable production of natural products from marine fungi has the potential to provide a renewable source of bioactive compounds with minimal environmental impact.The detailed structures of some important natural products from marine fungi are presented in Figure 5 and Table 6.Penicillium is a genus of fungi that includes several species known for their ability to produce a wide range of bioactive compounds, and it is the source of the first antibiotic, penicillin [157][158][159].In particular, marine Penicillium species have gained increasing attention in recent years due to their unique properties to produce novel bioactive compounds [160].They are found in various marine habitats, including sediments, mangroves, coral reefs, and seawater.A considerable number of studies have provided evidence of the bioactivity of compounds from Penicillium fungi; however, only few studies highlighted the importance of antifungal therapy.Here, some of the compounds with antifungal properties are reported.For example, pyrrospirones C-I (C249-C255) (Penicillium sp.ZZ380) are an uncommon class of alkaloids that inhibited the growth of C. albicans [147].Melearoride A (C260) and B (C266) from Penicillium meleagrinum var.viridiflavum had activity against C. albicans and synergistic interaction with fluconazole against azole-resistant C. albicans [150].Similar research was conducted by Kaleem et al. (2020), which resulted in the identification of 16 compounds, including andrastones B (C277) and C (C278), that had greater anti-candidal action [161].
Although natural products from sponges and other marine organisms are well known for their antifungal activities [173], many concerns still remain over their other features, including structural complexity, supply and availability, standardization and quality control, possible drug-drug interactions, side effects, toxicity, and lack of clinical evidence [11].Among them, supply chain management is the primary concern because extracting a single molecule from a complex mixture is a long and thorough process.
To overcome the supply chain management, great attention has been given to in situ cultivation and aquaculture [11].By adopting these methods, researchers can stimulate appropriate culture conditions without disrupting biodiversity, providing access to diverse sources of raw materials for a constant supply.In addition, both methods contribute to the standardized production of raw materials, facilitating the processes involved in the research and development of marine products.
An understanding of the complex structure of bioactive compounds can also provide insights into the production of similar kinds of chemical compounds.Chemical synthesis through which natural products are reproduced from different sources offers the option to obtain a product with comparably lesser cost than a product originating from its source [12,16,17].
We expect that this review can prompt researchers to establish biobanks and sample repositories of marine products with antifungal activities, promoting international collaborations and advances for the future application of marine natural products on Candida infections.

Conclusions
The need for new anti-candidal compounds has increased due to the emergence of various drug-resistant isolates; meanwhile, knowledge of different ecosystems can provide insights into drug discovery.The marine environment is being recognized as the treasure trove of novel chemical cues, whose potency, detailed structures, and functional properties still need to be explored as they are in terrestrial sources.
In summary, we found that sponges, algae, and microorganisms have been the major marine sources employed to extract metabolites with potential antifungal action, although many other organisms can also provide important sources of antifungal activity.According to the studies reported, a wide number of natural compounds from the marine environment were found to be effective against clinical and reference strains of C. albicans and non-albicans species, including C. auris, a multi-drug-resistant species.Several compounds showed stronger antifungal activity than conventional antifungal drugs, such as fluconazole and amphotericin B. Interestingly, some of these compounds had synergistic interaction with antifungal drugs and altered the resistance mechanisms, making the Candida cells more susceptible to fluconazole and echinocandins.In addition to antifungal activity, certain compounds showed activity against bacteria and immunomodulatory effects, which can potentialize its effects in the treatment of candidiasis since this infection can be associated with the presence of bacteria and immunodeficiency.
Although many antifungal compounds had already been isolated from marine organisms, most studies are limited to verifying their antifungal activity in in vitro models.To translate these compounds into clinical applications, there is still a long way to go, with the development of in vivo studies, toxicity assays, and investigations of action mechanisms.Moreover, some marine organisms are protected by international law in specific regions of the world, and it is uncertain whether there are enough raw materials to ensure a steady supply of natural products.Thus, new approaches are needed to address the issues related to the sustainable production and marketing of natural products using contemporary technologies to preserve maritime ecosystems.

Figure 1 .
Figure 1.List of FDA-approved natural products from marine resources and their year of approval.

Figure 2 .
Figure 2. Marine organisms for the isolation of different marine natural products.

Figure 1 .
Figure 1.List of FDA-approved natural products from marine resources and their year of approval.

Figure 2 .
Figure 2. Marine organisms for the isolation of different marine natural products.Figure 2. Marine organisms for the isolation of different marine natural products.

Figure 2 .
Figure 2. Marine organisms for the isolation of different marine natural products.Figure 2. Marine organisms for the isolation of different marine natural products.

Figure 3 .
Figure 3. Marine natural products from marine sponges.

Figure 3 .
Figure 3. Marine natural products from marine sponges.Red circle is an indicative of R group.

Figure 4 .
Figure 4. Marine natural products from marine actinomycetes.

Figure 4 .
Figure 4. Marine natural products from marine actinomycetes.Red circle is an indicative of R group.

Figure 5 .
Figure 5. Marine natural products from marine fungi.

Table 1 .
Natural products isolated from the samples of marine sponge and their activity against different Candida spp.

Table 1 .
Natural products isolated from the samples of marine sponge and their activity against different Candida spp.

Table 2 .
Natural products isolated from the samples of marine algae and their activity against different Candida spp.

Table 3 .
Natural products isolated from the samples of sea cucumber and their activity against different Candida spp.

Table 4 .
Natural products isolated from the samples of marine actinomycetes and their activity against different Candida spp.

Table 4 .
Natural products isolated from the samples of marine actinomycetes and their activity against different Candida spp.

Table 5 .
Natural products isolated from the samples of marine bacteria and their activity against different Candida sp.

Table 6 .
Natural compounds isolated from the samples of marine fungi and their activity against different Candida spp.

Table 6 .
Natural compounds isolated from the samples of marine fungi and their activity against different Candida spp.