Abstract
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.
Keywords: marine natural products, structural elucidation, antifungal properties
1. 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].
During the past few decades (1965–2021), only 17 of the purified chemical constituents from marine environments were recognized by US FDA for the prophylaxis of simple to life-threatening clinical conditions (Figure 1). Recently (between 2020 and 2021), lurbinectedin (ZepzelcaTM), belantamab mafodotin-blmf (Blenrep™), disitamab vedotin (Aidixi™), and tisotumab vedotin-tftv (TIVDAK™) obtained from tunicate and mollusk/cyanobacterium were approved for differential treatment of most common cancers, including metastatic cervical cancer, metastatic small cell lung cancer, and multiple myeloma [18]. In addition, there are 6 compounds in Phase III (originating from fungi, bacteria, puffer fish, tunicate, mollusk, and cyanobacteria), 15 in Phase II (originating from mollusk, cyanobacteria, sponge, and bryozoan), and 16 in Phase I (originating from mollusk, cyanobacteria, sponge, and red algae) stages of clinical trials. Besides the anticancer activity of the listed compounds, few other compounds have proven their effectiveness against chronic pain (tetrodotoxin) [19], coronavirus (plitidepsin) [20], relapsed or refractory systemic amyloidosis (STI-6129) [21], Alzheimer’s disease (bryostatin) [22], and HIV prevention and COVID-19 prophylaxis [23].
Figure 1.
List of FDA-approved natural products from marine resources and their year of approval. (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).
Figure 2.
Marine organisms for the isolation of different marine natural products.
2. Marine Natural Products
2.1. 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.
Figure 3.
Marine natural products from marine sponges. Red circle is an indicative of R group.
Table 1.
Natural products isolated from the samples of marine sponge and their activity against different Candida spp.
Compound | Source | ZOI (mm) |
MIC (µg/mL) and Activities |
Target Organism | Reference | |
---|---|---|---|---|---|---|
C1 | Oceanapiside | Oceanapia phillipensis | 10 | Cg | Dalisay et al., 2021 [27] | |
C2 | Oceanalin B | Oceanapia sp. | 25 | Cg | Makarieva et al., 2021 [28] | |
C3 | Pseudoceroxime A | Pseudoceratina sp. | 11.9 | Ca | Chen et al., 2020 [29] | |
C4 | Pseudoceroxime B | 13 | ||||
C5 | Pseudoceroxime C | 19.80 | ||||
C6 | Pseudoceroxime D | >20 | ||||
C7 | Pseudoceroxime E | >20 | ||||
C8 | Hippolide J | Hippospongia lachne | 0.125–4 | Ca, Cp, and Cg | Jiao et al., 2017 [30] | |
C9 | Zamamidine D | Amphimedon sp. | 16 | Ca | Kubota et al., 2017 [31] | |
C10 | Nakamurine A | Agelas nakamurai | Ca | Chu et al., 2017 [32] | ||
C11 | Nakamurine B | 60 | Ca | Chu et al., 2017 [32] | ||
C12–C14 | (Z)-5-(4-hydroxybenzylidene)-imidazolidine-2,4-dione, hemimycalins A and B | Hemimycale arabica | 22, 14, and 20 | Ca | Youssef et al., 2015 [33] | |
C15 | Crambescin | Pseudaxinella reticulate | 11–39; 6.1–17; 11–34 | Ca, Cg, and Ck | Jamison and Molinski, 2015 [34] | |
C16 | Theonellamide G | Theonella swinhoei | 4.49 and 2.0 | Ca | Youssef et al., 2014 [35] | |
C17 | Phorbasin H | 250 Targeting of yeast-to-hypha transition |
Ca | Lee et al., 2013 [36] | ||
C18–C19 | Nagelamide U and W | Agelas sp. | 4 | Ca | Tanaka et al., 2013a [37] | |
C20–C22 | Nagelamide X-Z | Agelas sp. | 0.25 to 2 | Ca | Tanaka et al., 2013b [38] | |
C23 | Aurantoside K | Melophlus | 31.25 and 1.95 | Ca | Kumar et al., 2012 [39] | |
C24 | Agelasine O | Agelas sp. | >32 | Ca | Kubota et al., 2012 [31] | |
C25 | Agelasine P | >32 | ||||
C26 | Agelasine Q | 16 | ||||
C27 | Agelasine R | 16 | ||||
C28 | Agelasine S | >32 | ||||
C29 | Agelasine T | >32 | ||||
C30 | Agelasine U | >32 | ||||
C31 | Woodylide A | Plakortis simplex | 32 | Ca | Yu et al., 2012 [40] | |
C32 | Aurantoside J | Theonella swinhoei | >16 | Ca, Cp, Cg, and Ct | Angawi et al., 2011 [41] | |
C33 | Ceratinadin A | Pseudoceratina sp. | 2 | Ca | Kon et al., 2010 [42] | |
C34 | Ceratinadin B | 4 | ||||
C35 | Ceratinadin C | >32 | ||||
C36–C37 | Pseudoceratin A and B |
Pseudoceratina purpurea | 8 and 6.55 | - | Ca | Jang et al., 2007 [39] |
C38 | Oceanalin A | Oceanapia sp. | 30 | Cg | Makarieva et al., 2005 [43] | |
C39 | 3,5-dibromo2-(3,5-dibromo-2-methoxyphenoxy) | Dysidea herbacea | 7.8, 7.8; 15.62 | Ca, Ct, and Cg | Sionov et al., 2005 [44] | |
C40–C41 | 9α,11α-epoxycholest-7-ene-3β,5α,6α,19-tetrol 6-acetate and agosterol A | Dysidea arenaria | Targeting of MDR1 and CDR1 | Ca | Jacob et al., 2003 [45] | |
C42–C43 | Bengamide Bengazole |
Pachastrissa sp. | 0.8 to 1.5 | Ca | Fernández et al., 1999 [46] | |
C44 | Aurantoside A | Siliquariaspongia japonica | 1.25 | Ca | Sata et al., 1999 [47] | |
C45 | Aurantoside B | 0.63 | ||||
C46 | Aurantoside D | 9.5 | ||||
C47 | Aurantoside E | 0.16 | ||||
C48 | Aurantoside F | Inactive | ||||
C49 | Microsclerodermin C | Theonella sp. | 5 | Ca | Schmidt, E. W., and Faulkner, 1998 [48] | |
C50 | Cyclolithistide A | Theonella swinhoei | 20 | Ca | Clark et al., 1998 [49] | |
C51–C52 | Phorboxazoles A and B |
Phorbas sp. | 12 | Ca | Searle et al., 1995 [50] | |
C53 | Theonegramide | Theonella swinhoei | 10 | Ca | Bewley, C. A., and Faulkner, 1994 [51] | |
C54 | Theonellamide F | Theonella sp. | 3–12 | unspecific Candida spp. | Matsunaga et al., 1989 [52] | |
C55 | Halichondramide | Halichondria sp. | 0.2 | Ca | Kernan et al., 1987 [53] |
Ca: Candida albicans; Ct: Candida tropicalis; Ck: Candida krusei; Cp: Candida parapsilosis; Cg: Candida glabrata; ZOI—zone of inhibition; MIC—minimum inhibitory concentration.
2.1.1. 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].
2.1.2. 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].
Nakamurines A (C10) and B (C11) are new non-brominated pyrrole alkaloids isolated from the sponge of Agelas nakamurai that exhibited antifungal activity against C. albicans, with a MIC of 60 μg/mL found for nakamurine B (C11) [32]. There are other relevant compounds extracted from Agelas sp., including bromopyrrole alkaloids, which demonstrated antifungal activity against C. albicans in a Caenorhabditis elegans model of candidiasis [55]; agelasines O-U (C24–C30) (diterpene alkaloids) with activity against C. albicans, exhibiting MIC values of 16–32 μg/mL [31]; nagelamides U (C18) and W (C19), which showed antifungal activity on C. albicans, with IC50 values of 4 μg/mL [37]; and nagelamides X-Z (C20–C22), which demonstrated strong activity against C. albicans (MIC values of 0.25 to 2 µg/mL) [38].
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].
2.1.3. 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 drug-resistant 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].
2.1.4. Steroids
Studies have revealed the antifungal activity of sulfated marine steroids, specifically 29-demethylgeodisterol-3-O-sulfite (C58) and geodisterol-3-O-sulfite (C59) extracted from the bioassay-guided fractionation of the extract of Topsentia sp., on C. albicans strains resistant to fluconazole. A pair of unusual antifungal molecules were reported from the marine sponge Hippospongia lachne with superior anticandidal activity [30]. Two sterols, 9α,11α-epoxycholest-7-ene-3β,5α,6α,19-tetrol 6-acetate (C40) and agosterol A (C41), which were isolated from the marine sponge Dysidea arenaria, have also shown activity against resistant Candida strains. These steroids showed strong inhibitory activity against efflux-mediated fluconazole-resistant strains of C. albicans. They directly target both MDR1 and CDR1 to reduce fluconazole resistance [45]. Another bioactive compound, 3,5-dibromo2-(3,5-dibromo-2-methoxyphenoxy) phenol (C39), isolated from the marine sponge Dysidea herbacea, exhibited significant anti-candidal activity (MIC of 7.8 µg/mL) by binding to the ergosterol of C. albicans and disrupting its membrane permeability. This compound also induced the leakage of potassium ions from Candida cells. Moreover, it displayed in vitro activity against C. tropicalis and C. glabrata, with MIC values of 7.8 µg/mL and 15.62 µg/mL, respectively [44].
2.1.5. 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].
2.1.6. Other Chemical Compounds
Finally, other chemical compounds from sponges showed significant antifungal activity against C. albicans, such as pseudoceratins A (C36) and B (C37) (bicyclic bromotyrosins) isolated from Pseudoceratina purpurea; pseudoceroxime A-C (C3–C5), and pseudocerolide D and E (C6, C7) (new bromotyrosine derivatives) extracted from Pseudoceratina sp. [60,61]; non-brominated racemic pyrrole derivatives from Agelas nakamurai [32]; and halichondramide (C55) from Chondrosia corticate [62].
2.2. Algae
Currently, there are over a million species of algae already known on Earth. Besides maintaining the CO2 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), 9-deoxyelatol (C64), isodactyloxene A (C65), and laurenmariallene (C66) from the species of red alga Laurencia mariannensis did not exhibit good anti-candidal activity [66].
Table 2.
Natural products isolated from the samples of marine algae and their activity against different Candida spp.
Compound | Source | ZOI (mm) |
MIC (µg/mL) and Activities | Target Organism | Reference | |
---|---|---|---|---|---|---|
Crude extract | Champia parvula | 13.8 ± 0.08 and 16.7 ± 0.15 | Ca, Ct | Ganesan 2019 [67] | ||
C67 | (9Z,12Z,15Z,18Z,21Z)-ethyl tetracosa-9,12,15,18,21- pentaenoate | Laurencia okamurai | 4 | Cg | Feng et al., 2015 [68] | |
C68 | Mahorone | Asparagopsis taxiformis | >32 | Ca | Greff et al., 2014 [69] | |
C69 | 5-bromomahorone | >32 | ||||
C70 | Laurepoxyene | Laurencia okamurai | 2 | Cg | Yu et al., 2014 [70] | |
C71 | 3b-Hydroperoxyaplysin | 4 | ||||
C72 | 3a-Hydroperoxy-3-epiaplysin | >64 | ||||
C73 | 8,10-Dibromoisoaplysin | >64 | ||||
C74 | (5S)-5-Acetoxy-b-bisabolene | 64 | ||||
C75 | 10-Bromoisoaplysin | 32 | ||||
C76 | Laurokamurene C | 1 | ||||
C77 | Laurokamurene A | 64 | ||||
C78 | Phlorotannin | Cystoseira nodicaulis Cystoseira usneoides and Fucus spiralis | 15.6 and 31.3; 31.3 and >62.5 | Ca; Ck | Lopes et al., 2013 [71] | |
C79 | Caulerprenylol B | Caulerpa racemosa | 4 | Cg | Liu et al., 2013 [72] | |
C80 | Bromophycolide U | >15 | Ca | Lin et al., 2010 [73] | ||
C81 | Isolauraldehyde | Laurencia obtusa | 70 | Ca | Alarif et al., 2012 [74] | |
C82 | 12-hydroxy isolaurene | 2000 | ||||
C83 | 8,11-dihydro-12-hydroxy isolaurene | 120 | ||||
C84 | Symphyocladin G | Symphyocladia latiuscula | 10 | Ca | Xu et al., 2012 [75] | |
C85 | Bromophycolide R | Callophycus serratus | >15 | Ca | Lin et al., 2010 [73] | |
C86 | Bromophycolide S | >15 | ||||
C87 | Bromophycolide T | >15 | ||||
C88 | 2,20,3,30-tetrabromo-4,40,5,50-tetrahydroxydiphenylmethane | Odonthalia corymbifera | 1.56 | Ca | Oh et al., 2008 [76] | |
C89–C90 | Capisterones A and B | Penicillus capitatus | CDR1 efflux pump activity | Ca | Li et al., 2006 [77] | |
C91 | Acetoxyfimbrolide | Delisea pulchra | 17 | Ca | Ankisetty et al., 2004 [78] |
Ca: Candida albicans; Ct: Candida tropicalis; Ck: Candida krusei; Cp: Candida parapsilosis; Cg: Candida glabrata; ZOI—zone of inhibition; MIC—minimum inhibitory concentration.
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].
2.3. 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.
Table 3.
Natural products isolated from the samples of sea cucumber and their activity against different Candida spp.
Compound | Group | Source | ZOI (mm) |
MIC (µg/mL) |
Target Organism | Reference | |
---|---|---|---|---|---|---|---|
C94
C95 C96 C97 C98 |
Coloquadranoside A Philinopside A Philinopside B Philinopside E Pentactaside B |
Triterpene glycosides | Colochirus quadrangularis | 4, 8, 4 20, 30, 32 4, 8, 4 4, 8, 4 25 |
Ca, Ct, and Cp | Yang et al., 2021 [79] | |
C99–C108 | Cousteside A-J | Non-sulfated triterpene glycosides | Bohadschia cousteaui | 10.7 ± 0.05 to 18.0 ± 0.01 | Ca | Elbandy et al., 2014 [80] | |
C109
C110 C111 C112 C113 C114 |
Variegatuside C Variegatuside D Variegatuside E Variegatuside F Variegatuside A Variegatuside B |
Triterpene glycosides | Stichopus variegates Semper | 12.5; 25; 12.5 3.4; 3.4; 13.6 25; 12.5; 12.5 25; 12.5; 12.5 25; 12.5; 12.5 100; 25; >125 |
Ca, Cp, and Ct | Wang et al., 2014 [81] | |
C115 | 26-Nor-25-oxo-holotoxin A1 | Triterpene glycosides | Apostichopus japonicus Selenka | >45.91 | Ca and Ct | Wang et al., 2012 [82] | |
C116 | Holotoxin D | 6.64, 13.29 | |||||
C117 | Holotoxin E | 13.45, 13.45 | |||||
C118 | Holotoxin F | 5.58, 5.68 | |||||
C119 | Holotoxin G | 5.81, 5.81 | |||||
C120 | Holotoxin A1 | 11.49, 5.68 | |||||
C121 | Holotoxin B | 11.36, 5.68 | |||||
C122 | Cladoloside B | 3.28, 1.64 | |||||
C123 | Arguside F | Triterpene glycosides | Holothuria (Microthele) axiloga | 64, 16, 16 | Ca, Ct, and Ck | Yuan et al., 2009a [83] | |
C124 | Impatienside B | 4, 4, 4 | |||||
C125 | Pervicoside D | 64, 16, 16 | |||||
C126
C127 C128 C129 C130 C131 |
Marmoratoside A Marmoratoside B 17α-hydroxy impatienside A 25-acetoxy bivittoside D Impatienside A Bivittoside D |
Triterpene glycosides | Bohadschia marmorata | 2.81; 2.81; 11.24 2.78; 2.78; 2.78 44.44; 44.44; 44.44 43.13; 10.78; 10.78 2.81; 2.81; 2.81 2.80; 2.80; 2.80 |
Ca, Ct, and Ck | Yuan et al., 2009b [84] | |
C132 | Axilogoside A (132) | Triterpene glycoside | Holothuria (Microthele) axiloga | 16 | Ca | Wei-Hua et al., 2008 [85] | |
C133 | Holothurin B (133) | Triterpene glycoside | Actinopyga lecanora | 25, 12.5 and 6.25 | Ca, Ck, and Cp | Kumar et al., 2007 [86] |
Ca: Candida albicans; Ct: Candida tropicalis; Ck: Candida krusei; Cp: Candida parapsilosis; Cg: Candida glabrata; ZOI—zone of inhibition; MIC—minimum inhibitory concentration.
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].
Furthermore, many other triterpene glycosides with activity against Candida species have been identified, including arguside F (C123), impatienside B (C124), and pervicoside D (C125) from sea cucumber Holothuria axiloga; marmoratoside A (C126) and B (C127), impatienside A (C130), and bivittoside D (C131) from Bohadschia marmorata [83,84]; and holothurin B (C133) from sea cucumber Actinopyga lecanora [86].
2.4. Bacteria
Marine bacteria live in an extremely complex environment with huge diversity. The ocean column consists of approximately 106 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.
2.4.1. 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.
Figure 4.
Marine natural products from marine actinomycetes. Red circle is an indicative of R group.
Table 4.
Natural products isolated from the samples of marine actinomycetes and their activity against different Candida spp.
Compound | Group | Source | ZOI (mm) |
MIC (µg/mL) and Activities | Target Organism | Reference | |
---|---|---|---|---|---|---|---|
C134
C135 C136 C137 C138 C139 |
Chainin Filipin IX Filipin XI Filipin XII Filipin II Filipin III |
Deep-sea actinobacteria | Streptomyces antibioticus OUCT16-2 | 1.56–12.5 | Ca | Bao et al., 2022 [92] | |
C140 | Antimycin I | Sponge-associated | Streptomyces sp. NBU3104 | 8 | Ca | Li et al., 2022 [93] | |
C141–C143 | Iseolide A–C | Coral-derived | Streptomyces sp. | 0.39–6.25 | Ca | Zhang et al., 2020 [94] | |
C144 | Tunicamycin C3 | Deep sea | Streptomyces xinghaiensis SCSIO S15077 | 4–32 | Ca | Zhang et al., 2020 [95] | |
C145 | Maculosin | Costa soil | Streptomyces sp. ZZ446 | 27 | Ca | Chen et al., 2020 [61] | |
C146 | Maculosin-O-a-L rhamnopyranoside | 26 | |||||
C147 | Rubromycin CA1 | Tunicate | Streptomyces hyaluromycini | 6.3 | Ca | Harunari et al., 2019 [96] | |
C148–C151 | Caniferolide A-D | Streptomyces caniferus CA-271066 | 0.5 to 2.0 | Ca | Pérez-Victoria et al., 2019 [97] | ||
C152–
C153 |
13(α)-Acetoxy-anhydroisoheximide and 13(β)-acetoxy-anhydroisoheximid | Deep sea | Streptomyces sp. YG7 | 62.5 | Ca | Pan 2019 [98] | |
C154–C156 | Nitricquinomycin A-C |
Marine-sediment-derived | Streptomyces sp. ZS-A45 | >40 | Ca | Zhou et al., 2019 [99] | |
C157–C160 | Streptopyrazinone A-D | Costal soil | Streptomyces sp. ZZ446 | 35–60 | Ca | Chen et al., 2018 [100] | |
C161 | N-acetyl-L-isoleucine-L-leucinamide | ||||||
C162–C165 | Strepoxepinmycin A–D |
Marine environment | Streptomyces sp. XMA39 | 5 to 10 | Ca | Jiang et al., 2018 [101] | |
C166–C168 | Kitamycin A-C | Streptomyces antibioticus strain 200-09 | 25 | Ca | Wang et al., 2017 [102] | ||
C169 | Urauchmycin B | ||||||
C170 | Deisovaleryblastomycin | ||||||
C171 | Rocheicoside A | Marine-sediment-derived | Streptomyces rochei 06CM016 | 37 | Ca | Aksoy et al., 2016 [103] | |
C172–C173 | Mohangamide A and B |
Marine actinomycete | Streptomyces sp. | inhibiting isocitrate lyase | IC50 = 4.4 and 20.5 µM | Ca | Bae et al. 2015 [104] |
C174–C175 | Reedsmycin A and F | Streptomyces sp. CHQ-64 | 25–50 | Ca | Che et al., 2015 [105] | ||
C176 | 28-N-Methylikaguramycin | Marine sediment | Streptomyces zhaozhouensis CA-185989 | 4 |
Ca | Lacret et al., 2014 [106] | |
C177 | Isoikarugamycin | 2–4 | |||||
C178 | Ikarugamycin | 4 | |||||
C179 | Caerulomycin A | Marine actinomycetes | Actinoalloateichus cyanogriseus | 0.39–0.78; 0.78–1.56 | Ca, Cg, and Ck | Ambavane et al., 2014 [107] | |
C180 | Arcticoside | Arctic Actinomycete | Streptomyces sp. | Inhibition of C. albicans Isocitrate Lyase | 30.4 μM | Ca | Moon et al., 2014 [108] |
C181 | Bahamaolide A | Marine actinomycete | Streptomyces sp. | 12.5 | Ca | Kim et al. 2012 [109] | |
C182 | (N-(2-hydroxyphenyl)-2-phenazinamine) | Arctic sediment | Nocardia dassonvillei | 64 | Ca | Gao et al., 2012 [110] | |
C183 | Azalomycin F4a 2-ethylpentyl ester | Mangrove rhizosphere soil | Streptomyces sp. 211726 | 2.34 and 12.5 | Ca | Yuan et al., 2013 [111] | |
C184 | Azalomycin F5a 2-ethylpentyl ester | ||||||
C185–C186 | Antimycins A19 and A20 |
Streptomyces antibioticus H74-18 | 5 to 10 | Ca | Xu et al., 2011 [112] | ||
C187 | Saadamycin | Egyptian sponge Aplysina fistularis | Streptomyces sp. Hedaya48 | 2.22 and 15 | Ca | El-Gendy and EL-Bondkly, 2010 [113] | |
C188 | 5,7-Dimethoxy-4-p-methoxylphenylcoumarin | ||||||
C189 | Chitinase | Sponge associate | Streptomyces sp. DA11 | 10.48 ± 0.45 | - | Ca | Han et al., 2009 [114] |
C190 | Caboxamycin | Deep sea cold water | Streptomyces sp. NTK 937 | - | 117 | Cg | Hohmann et al., 2009 [115] |
C191 | Piperazimycin B | Marine-derived | Streptomyces sp. | 14 | - | Ca | Shaaban et al., 2008 [116] |
Ca: Candida albicans; Ct: Candida tropicalis; Ck: Candida krusei; Cp: Candida parapsilosis; Cg: Candida glabrata; ZOI—zone of inhibition; MIC—minimum inhibitory concentration.
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.
Streptomyces antibioticus OUCT16-23 strain isolated from a deep-sea sediment sample produces macrolides that displayed antifungal activity against C. albicans [92]. Streptomyces sp. ZZ446 from coastal soil produces different compounds, namely streptopyrazinones A-D (C157–C160), which exhibited activity against C. albicans and methicillin-resistant Staphylococcus aureus [100,121]. Caniferolides A-D (C148–C151) from marine-derived Streptomyces caniferus CA-271066 showed antifungal activity against C. albicans, with MIC values ranging from 0.5 to 2.0 µg/mL, which were comparably lesser than the MIC of amphotericin B (2–4 µg/mL). Despite its antifungal activity, caniferolides had a high antiproliferative activity on tumor cell lines [97]. Streptomyces xinghaiensis SCSIO S15077 produce tunicamycin derivatives with antifungal activity against both fluconazole-resistant and sensitive C. albicans isolates, with emphasis on tunicamycin C3 (C144), which showed MIC values of 4 and 2 μg/mL. A bioassay-guided fraction from Streptomyces sp. YG7 yielded two new epimers of cycloheximide with moderate activity against C. albicans (a MIC value of 62.5) [98,122].
Many other antifungal compounds produced by Streptomyces spp. have been isolated, including nitricquinomycins A–C (C154–C156) [99]; rocheicoside A (C171) [103]; 28-N-methylikaguramycin (C176), isoikarugamycin (C177), and ikarugamycin (C178) [106]; caboxamycin (C190) [115]; and piperazimycin B (C191) [116]. Besides Streptomyces, other bacteria have also been explored. The bioactive fraction of Actinoalloateichus sp. exhibited a broad spectrum of anti-candidal activity. Further structural characterization identified caerulomycin A (C179) as an active metabolite, with MIC values of 0.78–1.56 μg/mL against fluconazole-resistant C. albicans, 0.39–0.78 μg/mL against C. glabrata, and 0.78–1.56 μg/mL against C. krusei [107]. An Arctic-sediment-derived actinomycete, Nocardia dassonvillei, produces extracellular substances rich in the secondary metabolite N-(2-hydroxyphenyl)-2-phenazinamine (C182), which showed antifungal activity against C. albicans, with a MIC value of 64 µg/mL [110].
2.4.2. Other Bacteria
High-throughput screening approaches have been routinely used to explore the secondary metabolites from many other marine bacteria with biological activity, as presented in Table 5. Examples include cycloprodigiosin (C192) (Pseudoalteromonas rubra), bulbimidazoles A−C (C193–C195) (Microbulbifer sp. DC3-6), and indolepyrazines A (C196) and B (C197) (Acinetobacter sp. ZZ1275), which were able to modify the susceptibility of C. albicans to antifungal drugs [123,124,125]. Recently, janthinopolyenemycins A (C198) and B (C199) (Janthinobacterium spp. ZZ145 and ZZ148) exhibited strong antifungal activity against C. albicans by expressing low MIC values [126]. The fermented broth of marine bacteria Bacillus licheniformis 09IDYM23 presented two anti-candidal glycolipids, ieodoglucomide C (C200) and ieodoglycolipid (C201), that also had activity against C. albicans [127]. Forazoline A (C202) and B (C203), derived from marine-invertebrate-associated bacteria, reduced the fungal burden level in mice infected with C. albicans [128]. Finally, the ethyl acetate extract of Bacillus subtilis yielded seven compounds, and all of them exhibited reasonable anti-candidal activity against C. albicans [129].
Table 5.
Natural products isolated from the samples of marine bacteria and their activity against different Candida sp.
Compound | Group | Source | ZOI (mm) | MIC (µg/mL) | Target Organism | Reference | |
---|---|---|---|---|---|---|---|
C192
C204 C205 |
Cycloprodigiosin Prodigiosin 2-Methyl-3-hexyl prodiginine |
Red marine bacterium | Pseudoalteromonas rubra | 7.9 ± 0.07, 8.2 ± 0.09 7.9 ± 0.06 | Ca | Setiyono et al., 2020 [123] | |
C193–C195 | Bulbimidazole A−C | Gammaproteobacterium Microbulbifer | 6.25–12.5 | Ca | Karim et al., 2020 [124] | ||
C196
C197 |
Indolepyrazine A Indolepyrazine B |
Marine bacteria | Acinetobacter sp. ZZ1275 | 12 and 14 | Ca | Anjum et al., 2019 [125] | |
C198
C199 |
Janthinopolyenemycin A Janthinopolyenemycin B | Marine bacteria | Janthinobacterium spp. ZZ145 and ZZ148 | 15.6 | Ca | Anjum et al., 2018 [126] | |
C200
C201 |
Ieodoglucomide C Ieodoglycolipid |
Marine bacteria | Bacillus licheniformis 09IDYM23 | 0.05 and 0.03 | Ca | Tareq et al., 2015 [127] | |
C202
C203 |
Forazoline A Forazoline B |
Invertebrate-associated bacteria | 16 | Ca | Wyche et al., 2014 [128] | ||
C204–C210
|
Gageomacrolactin A-C, macrolactins A (C207), B (C208), E (C209) and W (C210) | Marine sediments | Bacillus subtilis | 0.05–0.15 | Ca | Tareq et al., 2013 [129] | |
C211–218 | Quinazolinones (in total 8 analogues) | Marine bacterium | Bacillu cereus 041381 | 1.3–15.6 | Ca | Xu et al., 2011 [130] | |
C219 | Pedein A | Chondromyces pediculatus | 32 | 1.6 | Ca | Kunze et al. 2008 [131] | |
C220 | 2-Nitro-4-(2′-nitroethenyl)-phenol | Arctic sea ice bacterium | Salegentibacter sp. T436 | 20 | Ca | Al-Zereini et al. 2007 [132] | |
C221 | Hassallidin A | Cyanobacterium | Hassallia sp. | 4.8 | Ca | Neuhof et al., 2005 [133] | |
C222
C223 |
Basiliskamide A Basiliskamide B |
Tropical marine habitat | Bacillus laterosporus | 1.0 3.1 |
Ca | Barsby et al., 2002 [134] | |
C224–C226 | Lobocyclamide A-C | Cyanobacterial mat | Lyngbya confervoides | 7–10 and 6–8 | Ca and Cg | MacMillan et al., 2002 [135] |
Ca: Candida albicans; Ct: Candida tropicalis; Ck: Candida krusei; Cp: Candida parapsilosis; Cg: Candida glabrata; ZOI—zone of inhibition; MIC—minimum inhibitory concentration.
2.5. 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 marine-derived 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.
Figure 5.
Marine natural products from marine fungi.
Table 6.
Natural compounds isolated from the samples of marine fungi and their activity against different Candida spp.
Compound | Group | Source | ZOI (mm) | MIC (µg/mL) | Target organism | Reference | |
---|---|---|---|---|---|---|---|
C227
C228 |
Ditalaromylectone A Altenusin |
Talaromyces mangshanicus BTBU20211089 | 200 | Ca | Zhang et al., 2022 [136] | ||
C229 | ent-Epiheveadride | Marine sediment | Aspergillus chevalieri PSU-AMF79 | 200 | Ca | Ningsih et al., 2022 [137] | |
C230 | (-)-Massoia lactone | Unidentified tunicate | Trichoderma harzianum PSU-MF79 | 200 | Ca | Nuansri et al., 2021 [138] | |
C231 | Talaroisocoumarin A | Marine-derived fungi | Talaromyces sp. ZZ1616 | 26 | Ca | Mingzhu Ma et al., 2020 [139] | |
C232 | Emethacin C | Tissue of sea hare aplysia pulmonica | Aspergillus terreus | 32 | Ca | Wu et al., 2020 [140] | |
C233–C235 | Trichobreol A-C | Marine red alga | Trichoderma cf. brevicompactum | 3.1- 50 | Ca | Yamazaki et al. 2020 [141] | |
C236 | Atranone Q | Marine fungus | Stachybotrys chartarum | 8 | Ca | Yang et al., 2019 [142] | |
C237 | Terretrione C | Tunicate-derived fungus | Penicillium sp. | 19 | 32 | Ca | Shaala LA and Youssef DT 2015 [143] |
C238
C239 |
Asperfurandione A Asperfurandione B |
Deep-sea fungi | Aspergillus versicolor | 64 | Ca | Ding et al., 2019 [144] | |
C240–C247 | Cladosporiumin A-H | Cladosporium sp. SCSIO z0025 | Anti-biofilm | Ca | Huang et al., 2018 [145] | ||
C248 | Eutypellenoid B | Arctic fungus | Eutypella sp. | 8, 16 and 32 | Ca, Cg, and Ct | Yu et al., 2018 [146] | |
C249–C255 | Pyrrospirones C-I | Marine-derived fungus | Penicillium sp. ZZ380. | No activity | Ca | Song et al., 2018 [147] | |
C256 | Nigerasperone C | Marine brown alga | Aspergillus niger EN-13 | 9.0 | - | Ca | Zhang et al., 2007 [148] |
C257 | Penicillenol | Marine sediment | Aspergillus restrictus DFFSCS006 | >200 | Ca | Wang et al., 2017 [149] | |
C258
C259 |
Penicillenol A2 Penicillenol B1 |
Marine sediment | Aspergillus restrictus DFFSCS006 | Inhibit the biofilm growth and hyphae-related genes | Ca | Wang et al., 2017 [149] | |
C260 | Melearoride A | Marine-derived fungus | Penicillium meleagrinum var. viridiflavum | >32 | Ca | Okabe et al., 2016 [150] | |
C261 | PF1163A | 1 | |||||
C262 | PF1163B | 2 | |||||
C263 | PF1163D | >32 | |||||
C264 | PF1163H | 16 | |||||
C265 | PF1163F | 8 | |||||
C266 | Melearoride B | >32 | |||||
C267
C268 |
Pleosporallin D Pleosporallin E |
Marine alga Enteromorpha clathrata | Pleosporales sp. | >10 7.44 |
Ca | Chen et al., 2015 [151] | |
C269 | Dendrodochol A | Sea cucumber | Dendrodochium sp. | 16, 16, 16 | Ca, Cp, and Cg | Xu et al., 2014 [152] | |
C270 | Dendrodochol B | 16, >64, >64 | |||||
C271 | Dendrodochol C | 16, 16, 8 | |||||
C272 | Dendrodochol D | > 64 all | |||||
C273 | Didymellamide A | Marine-sponge-associated | Stagonosporopsis cucurbitacearum | 3.1; 3.1 | Ca and Cg | Haga et al., 2013 [153] | |
C274 | Citrafungin A | Marine fungi | Aspergillus aculeatus | 0.43 | Ca | Singh 2004 [154] | |
C275
C276 |
Sporiolide A Sporiolide B |
Brown alga Actinotrichia fragilis | Cladosporium sp. | 16.7 >33.33 |
Ca | Shigemori et al., 2004 [155] | |
C277 | Xestodecalactone A | Marine-sponge-associated | Penicillium cf. montanense | 7, 12 and 25 | 20, 50 and 100 | Ca | Edrada et al., 2002 [156] |
Ca: Candida albicans; Ct: Candida tropicalis; Ck: Candida krusei; Cp: Candida parapsilosis; Cg: Candida glabrata; ZOI—zone of inhibition; MIC—minimum inhibitory concentration.
2.5.1. Penicillium spp.
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].
2.5.2. Endophytic Fungi
Amongst endophytic fungi, Cladosporium sp. was found to have two isolated compounds with biological activity: sporiolides A (C274) exhibited strong activity against C. albicans, with a concentration of 16.7 µg/mL, and sporiolides B (C275) showed moderate cytotoxicity against murine lymphoma L1210 cells [155]. Endophytic Aspergillus niger EN-13 produced nigerasperone C (C256), with moderate activity against C. albicans [148]. Furthermore, biologically active molecules didymellamide A (C272) and B-D (C279–C281) (Stagonosporopsis cucurbitacearum), as well as pleosporallin D (C267) and E (C268) (Pleosporales sp.), were obtained from different endophytic marine fungi with activity against C. albicans [151,153]. Aspergillus sp. is associated with sponge-produced tetrahydrofuran derivative known as aspericacid B (C282) but it exhibited no activity towards Candida. An another study reported that terretrione C (C237) from tunicate-derived fungus, Penicillium sp. CYE-87 was active against C. albicans with the MIC of 32 µg/mL [143]. Sponge-derived endophytic fungus Fusarium sp. LY019 yielded two alkaloids, fusaripyridines A (C283) and B (C284), that were identified as inhibitors of C. albicans growth, but they were not active against certain bacteria and HeLa cells [162]. Other promising antifungal compounds against C. albicans are the new thiodiketopiperazine (C285), epipolythiodiketopiperazine (C286), and trichothecene (C287) derivatives from Aspergillus terreus and Trichoderma cf. brevicompactum, respectively [140,141].
2.5.3. Other Fungi
Recently, several new metabolites such as talaromydien A (C288) and talaroisocoumarin A (C231) were isolated from Talaromyces sp. ZZ1616. Talaroisocoumarin A (C231) expressed superior activity against C. albicans (26 µg/mL) and some bacterial species [139]. Furthermore, bioactive compounds of Aspergillus fumigatus were effective against C. albicans with a MIC of >100 µM [163]. Similar observations were made by Ding et al. and Huang et al. (2018), who proved the efficacy of secondary metabolites against C. albicans obtained from Aspergillus versicolor and Cladosporium sp. SCSIO z0025, respectively [144,145]. Ditalaromylectones A (C227) and B (C289), along with seven known compounds, were isolated from Talaromyces mangshanicus BTBU20211089, but only ditalaromylectone A (C227) was active against C. albicans [136]. Ent-epiheveadride (C229), a new nonadride enantiomer isolated from the marine fungus Aspergillus chevalieri PSU-AMF79, had moderate inhibitory activity against C. albicans with a MIC value of 200 µg/mL [137].
2.6. Miscellaneous
The marine sources of antifungal compounds are not limited to sponges, algae, sea cucumbers, bacteria, and fungi, but there are some other important sources from the marine environment, such as corals, mollusks, coelenterates, and bryozoans. For example, iseolide A (C241) (isolated from coral-derived actinomycete Streptomyces sp.) [94] and nocarimidazoles C (C290) and D (C291) (isolated from coral-derived actinomycete Kocuria sp.) [164,165] demonstrated activity against C. albicans. Polyketides are unique structures isolated from dinoflagellate Amphidinium carterae, with proven antifungal activity [166]. Similarly, Didemnum sp. collected from the Red Sea produce didemnaketals F (C292) and G (C293), which were able to control the growth of C. albicans at a concentration of 100 µg/disc with a zone of inhibition of 16–24 mm [167]. Apart from this, several studies reported some compounds with potential antifungal action from marine snail Cenchritis muricatus [168], sea squirt Ciona intestinalis [169], tunicate Halocynthia aurantium [170], ascidian Clavelina oblonga [171], and tunicate Eudistoma sp. [172].
3. Discussion and Future Perspectives
In this review, among the data collected from different studies focused on marine organisms, sponges, algae, bacteria, and fungi seem to be the major contributors of bioactive compounds with anti-candidal activity. Promisingly, marine sponges stand out due to having a large number of biologically important molecules [24]. In particular, sponges have been recognized as prolific producers of alkaloids, terpenoids, peptides, polyketides, and sterols, among others [31,32,33,36,37,38,42,44,48,49,50,51,55,56]. All these classes of molecules exhibit significant biological activities against Candida species [24,25,26,27,28,43,47,54].
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.
4. 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.
Author Contributions
All authors have contributed equally. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article.
Conflicts of Interest
The authors declare no conflict of interest.
Funding Statement
Coordination Improvement of Higher Education Personnel (CAPES/Brazil): 88887.695977/2022-00; National Council for Scientific and Technological Development: (CNPq/Brazil): 310265/2022-3.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
References
- 1.Azanza J.R., Grau S., Vázquez L., Rebollo P., Peral C., López-Ibáñez de Aldecoa A., López-Gómez V. The cost-effectiveness of isavuconazole compared to voriconazole, the standard of care in the treatment of patients with invasive mould diseases, prior to differential pathogen diagnosis in Spain. Mycoses. 2021;64:66–77. doi: 10.1111/myc.13189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Brown G.D., Denning D.W., Gow N.A.R., Levitz S.M., Netea M.G., White T.C. Hidden Killers: Human Fungal Infections. Sci. Transl. Med. 2012;4:165. doi: 10.1126/scitranslmed.3004404. [DOI] [PubMed] [Google Scholar]
- 3.Richardson M.D. Changing patterns and trends in systemic fungal infections. J. Antimicrob. Chemother. 2005;56:i5–i11. doi: 10.1093/jac/dki218. [DOI] [PubMed] [Google Scholar]
- 4.Fisher M.C., Gurr S.J., Cuomo C.A., Blehert D.S., Jin H., Stukenbrock E.H., Stajich J.E., Kahmann R., Boone C., Denning D.W., et al. Threats Posed by the Fungal Kingdom to Humans, Wildlife, and Agriculture. mBio. 2020;11:e00449-20. doi: 10.1128/mBio.00449-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ocansey B.K., Pesewu G.A., Codjoe F.S., Osei-Djarbeng S., Feglo P.K., Denning D.W. Estimated Burden of Serious Fungal Infections in Ghana. J. Fungi. 2019;5:38. doi: 10.3390/jof5020038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gintjee T.J., Donnelley M.A., Thompson G.R. Aspiring Antifungals: Review of Current Antifungal Pipeline Developments. J. Fungi. 2020;6:28. doi: 10.3390/jof6010028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Fuentefria A., Pippi B., Lana D.D., Donato K., de Andrade S. Antifungals discovery: An insight into new strategies to combat antifungal resistance. Lett. Appl. Microbiol. 2018;66:2–13. doi: 10.1111/lam.12820. [DOI] [PubMed] [Google Scholar]
- 8.Morio F., Jensen R.H., Le Pape P., Arendrup M.C. Molecular basis of antifungal drug resistance in yeasts. Int. J. Antimicrob. Agents. 2017;50:599–606. doi: 10.1016/j.ijantimicag.2017.05.012. [DOI] [PubMed] [Google Scholar]
- 9.Lee Y., Puumala E., Robbins N., Cowen L.E. Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond. Chem. Rev. 2020;121:3390–3411. doi: 10.1021/acs.chemrev.0c00199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kołaczkowska A., Kołaczkowski M. Drug resistance mechanisms and their regulation in non-albicans Candida species. J. Antimicrob. Chemother. 2016;71:1438–1450. doi: 10.1093/jac/dkv445. [DOI] [PubMed] [Google Scholar]
- 11.Atanasov A.G., Zotchev S.B., Dirsch V.M., Supuran C.T. Natural products in drug discovery: Advances and opportunities. Nat. Rev. Drug Discov. 2021;20:200–216. doi: 10.1038/s41573-020-00114-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.König G.M., Kehraus S., Seibert S.F., Abdel-Lateff A., Müller D. Natural products from marine organisms and their asso-ciated microbes. ChemBioChem. 2006;7:229–238. doi: 10.1002/cbic.200500087. [DOI] [PubMed] [Google Scholar]
- 13.Calixto J.B. The role of natural products in modern drug discovery. An. Acad. Bras. Ciênc. 2019;91:e20190105. doi: 10.1590/0001-3765201920190105. [DOI] [PubMed] [Google Scholar]
- 14.Carroll A.R., Copp B.R., Davis R.A., Keyzers R.A., Prinsep M.R. Marine natural products. Nat. Prod. Rep. 2019;36:122–173. doi: 10.1039/C8NP00092A. [DOI] [PubMed] [Google Scholar]
- 15.Khalifa S.A.M., Elias N., Farag M.A., Chen L., Saeed A., Hegazy M.-E.F., Moustafa M.S., El-Wahed A.A., Al-Mousawi S.M., Musharraf S.G., et al. Marine Natural Products: A Source of Novel Anticancer Drugs. Mar. Drugs. 2019;17:491. doi: 10.3390/md17090491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Gandhi S.G., Mahajan V., Bedi Y.S. Changing trends in biotechnology of secondary metabolism in medicinal and aromatic plants. Planta. 2014;241:303–317. doi: 10.1007/s00425-014-2232-x. [DOI] [PubMed] [Google Scholar]
- 17.Shahnawaz M., editor. Biotechnological Approaches to Enhance Plant Secondary Metabolites: Recent Trends and Future Pro-spects. CRC Press; Boca Raton, FL, USA: 2022. [Google Scholar]
- 18.Marine Pharmacology Mysite. [(accessed on 10 July 2023)]. Available online: https://www.marinepharmacology.org/
- 19.Nieto F.R., Cobos E.J., Tejada M., Sánchez-Fernández C., González-Cano R., Cendán C.M. Tetrodotoxin (TTX) as a Therapeutic Agent for Pain. Mar. Drugs. 2012;10:281–305. doi: 10.3390/md10020281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Martinez M.A. Plitidepsin: A Repurposed Drug for the Treatment of COVID-19. Antimicrob. Agents Chemother. 2021;65 doi: 10.1128/AAC.00200-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Bal S., Landau H. AL amyloidosis: Untangling new therapies. Hematology. 2021;2021:682–688. doi: 10.1182/hematology.2021000305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Thompson R.E., Tuchman A.J., Alkon D.L. Bryostatin Placebo-Controlled Trials Indicate Cognitive Restoration Above Base-line for Advanced Alzheimer’s Disease in the Absence of Memantine. J. Alzheimer’s Dis. 2022;86:1221–1229. doi: 10.3233/JAD-215545. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Cai Y., Xu W., Gu C., Cai X., Qu D., Lu L., Xie Y., Jiang S. Griffithsin with A Broad-Spectrum Antiviral Activity by Binding Glycans in Viral Glycoprotein Exhibits Strong Synergistic Effect in Combination with A Pan-Coronavirus Fusion Inhibitor Targeting SARS-CoV-2 Spike S2 Subunit. Virol Sin. 2020;35:857–860. doi: 10.1007/s12250-020-00305-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Anjum K., Abbas S.Q., Shah S.A.A., Akhter N., Batool S., Hassan S.S.U. Marine Sponges as a Drug Treasure. Biomol. Ther. 2016;24:347–362. doi: 10.4062/biomolther.2016.067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Thomas T.R.A., Kavlekar D.P., LokaBharathi P.A. Marine Drugs from Sponge-Microbe Association—A Review. Mar. Drugs. 2010;8:1417–1468. doi: 10.3390/md8041417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hertiani T., Edrada-Ebel R., Ortlepp S., van Soest R.W., de Voogd N.J., Wray V., Hentschel U., Kozytska S., Müller W.E., Proksch P. From anti-fouling to biofilm inhibition: New cytotoxic secondary metabolites from two Indonesian Agelas sponges. Bioorganic Med. Chem. 2010;18:1297–1311. doi: 10.1016/j.bmc.2009.12.028. [DOI] [PubMed] [Google Scholar]
- 27.Dalisay D.S., Rogers E.W., Molinski T.F. Oceanapiside, a marine natural product, targets the sphingolipid pathway of flu-conazole-resistant Candida glabrata. Mar. Drugs. 2021;19:126. doi: 10.3390/md19030126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Makarieva T.N., Ivanchina N.V., Dmitrenok P.S., Guzii A.G., Stonik V.A., Dalisay D.S., Molinski T.F. Oceanalin B, a Hybrid α, ω-Bifunctionalized Sphingoid Tetrahydroisoquinoline β-Glycoside from the Marine Sponge Oceanapia sp. Mar. Drugs. 2021;19:635. doi: 10.3390/md19110635. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ahirwar A., Kesharwani K., Deka R., Muthukumar S., Khan M.J., Rai A., Vinayak V., Varjani S., Joshi K.B., Morjaria S. Microalgal drugs: A promising therapeutic reserve for the future. J. Biotechnol. 2022;349:32–46. doi: 10.1016/j.jbiotec.2022.03.012. [DOI] [PubMed] [Google Scholar]
- 30.DiGirolamo J.A., Li X.-C., Jacob M.R., Clark A.M., Ferreira D. Reversal of Fluconazole Resistance by Sulfated Sterols from the Marine Sponge Topsentia sp. J. Nat. Prod. 2009;72:1524–1528. doi: 10.1021/np900177m. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Kubota T., Iwai T., Takahashi-Nakaguchi A., Fromont J., Gonoi T., Kobayashi J. Agelasines O–U, new diterpene alkaloids with a 9-N-methyladenine unit from a marine sponge Agelas sp. Tetrahedron. 2012;68:9738–9744. doi: 10.1016/j.tet.2012.09.040. [DOI] [Google Scholar]
- 32.Chu M.-J., Tang X.-L., Qin G.-F., Sun Y.-T., Li L., de Voogd N.J., Li P.-L., Li G.-Q. Pyrrole Derivatives and Diterpene Alkaloids from the South China Sea Sponge Agelas nakamurai. Chem. Biodivers. 2017;14:e1600446. doi: 10.1002/cbdv.201600446. [DOI] [PubMed] [Google Scholar]
- 33.Youssef D.T.A., Shaala L.A., Alshali K.Z. Bioactive Hydantoin Alkaloids from the Red Sea Marine Sponge Hemimycale arabica. Mar. Drugs. 2015;13:6609–6619. doi: 10.3390/md13116609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Jamison M.T., Molinski T.F. Antipodal crambescin A2 homologues from the marine sponge Pseudaxinella reticulata. Anti-fungal structure–activity relationships. J. Nat. Prod. 2015;78:557–561. doi: 10.1021/np501052a. [DOI] [PubMed] [Google Scholar]
- 35.Youssef D.T., Shaala L.A., Mohamed G.A., Badr J.M., Bamanie F.H., Ibrahim S.R. Theonellamide G, a potent antifungal and cytotoxic bicyclic glycopeptide from the Red Sea marine sponge Theonella swinhoei. Mar. Drugs. 2014;12:1911–1923. doi: 10.3390/md12041911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Lee S.-H., Jeon J.-E., Ahn C.-H., Chung S.-C., Shin J., Oh K.-B. Inhibition of yeast-to-hypha transition in Candida albicans by phorbasin H isolated from Phorbas sp. Appl. Microbiol. Biotechnol. 2012;97:3141–3148. doi: 10.1007/s00253-012-4549-3. [DOI] [PubMed] [Google Scholar]
- 37.Tanaka N., Kusama T., Takahashi-Nakaguchi A., Gonoi T., Fromont J., Kobayashi J. Nagelamides U–W, bromopyrrole alkaloids from a marine sponge Agelas sp. Tetrahedron Lett. 2013;54:3794–3796. doi: 10.1016/j.tetlet.2013.05.023. [DOI] [PubMed] [Google Scholar]
- 38.Tanaka N., Kusama T., Takahashi-Nakaguchi A., Gonoi T., Fromont J., Kobayashi J.I. Nagelamides X–Z, dimeric bro-mopyrrole alkaloids from a marine sponge Agelas sp. Org. Lett. 2013;15:3262–3265. doi: 10.1021/ol401291n. [DOI] [PubMed] [Google Scholar]
- 39.Kumar R., Subramani R., Feussner K.-D., Aalbersberg W. Aurantoside K, a New Antifungal Tetramic Acid Glycoside from a Fijian Marine Sponge of the Genus Melophlus. Mar. Drugs. 2012;10:200–208. doi: 10.3390/md10010200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Yu H.-B., Liu X.-F., Xu Y., Gan J.-H., Jiao W.-H., Shen Y., Lin H.-W. Woodylides A–C, New Cytotoxic Linear Polyketides from the South China Sea Sponge Plakortis simplex. Mar. Drugs. 2012;10:1027–1036. doi: 10.3390/md10051027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Angawi R.F., Bavestrello G., Calcinai B., Dien H.A., Donnarumma G., Tufano M.A., Paoletti I., Grimaldi E., Chianese G., Fattorusso E., et al. Aurantoside J: A new tetramic acid glycoside from Theonella swinhoei. Insights into the antifungal potential of aurantosides. Mar. Drugs. 2011;9:2809–2817. doi: 10.3390/md9122809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Kon Y., Kubota T., Shibazaki A., Gonoi T., Kobayashi J.I. Ceratinadins A–C, new bromotyrosine alkaloids from an Oki-nawan marine sponge Pseudoceratina sp. Bioorganic Med. Chem. Lett. 2010;20:4569–4572. doi: 10.1016/j.bmcl.2010.06.015. [DOI] [PubMed] [Google Scholar]
- 43.Makarieva T.N., Denisenko V.A., Dmitrenok P.S., Guzii A.G., Santalova E.A., Stonik V.A., Molinski T.F. Oceanalin A, a hybrid α, ω-bifunctionalized sphingoid tetrahydroisoquinoline β-glycoside from the marine sponge Oceanapia sp. Org. Lett. 2005;7:2897–2900. doi: 10.1021/ol050796c. [DOI] [PubMed] [Google Scholar]
- 44.Sionov E., Roth D., Sandovsky-Losica H., Kashman Y., Rudi A., Chill L., Berdicevsky I., Segal E. Antifungal effect and possible mode of activity of a compound from the marine sponge Dysidea herbacea. J. Infect. 2005;50:453–460. doi: 10.1016/j.jinf.2004.07.014. [DOI] [PubMed] [Google Scholar]
- 45.Jacob M.R., Hossain C.F., Mohammed K.A., Smillie T.J., Clark A.M., Walker L.A., Nagle D.G. Reversal of Fluconazole Resistance in Multidrug Efflux-Resistant Fungi by the Dysidea a renaria Sponge Sterol 9α, 11α-Epoxycholest-7-ene-3β, 5α, 6α, 19-tetrol 6-Acetate. J. Nat. Prod. 2003;66:1618–1622. doi: 10.1021/np030317n. [DOI] [PubMed] [Google Scholar]
- 46.Fernández R., Dherbomez M., Letourneux Y., Nabil M., Verbist J.F., Biard J.F. Antifungal metabolites from the marine sponge Pachastrissa sp.: New bengamide and bengazole derivatives. J. Nat. Prod. 1999;62:678–680. doi: 10.1021/np980330l. [DOI] [PubMed] [Google Scholar]
- 47.Sata N.U., Matsunaga S., Fusetani N., van Soest R.W. Aurantosides D, E, and F: New Antifungal Tetramic Acid Glycosides from the Marine Sponge Siliquariaspongiajaponica. J. Nat. Prod. 1999;62:969–971. doi: 10.1021/np9900021. [DOI] [PubMed] [Google Scholar]
- 48.Schmidt E.W., Faulkner D.J. Microsclerodermins C–E, antifungal cyclic peptides from the lithistid marine sponges Theonella sp. and Microscleroderma sp. Tetrahedron. 1998;54:3043–3056. doi: 10.1016/S0040-4020(98)00054-4. [DOI] [Google Scholar]
- 49.Clark D.P., Carroll J., Naylor S., Crews P. An antifungal cyclodepsipeptide, cyclolithistide A, from the sponge Theonella swinhoei. J. Org. Chem. 1998;63:8757–8764. doi: 10.1021/jo980758p. [DOI] [Google Scholar]
- 50.Searle P.A., Molinski T.F. Phorboxazoles A and B: Potent cytostatic macrolides from marine sponge Phorbas species. J. Am. Chem. Soc. 1995;117:8126–8131. doi: 10.1021/ja00136a009. [DOI] [Google Scholar]
- 51.Bewley C.A., Faulkner D.J. Theonegramide, an Antifungal Glycopeptide from the Philippine Lithistid Sponge Theonella swinhoei. J. Org. Chem. 1994;59:4849–4852. doi: 10.1021/jo00096a028. [DOI] [Google Scholar]
- 52.Matsunaga S., Fusetani N., Hashimoto K., Walchli M., Theonellamide F. A novel antifungal bicyclic peptide from a marine sponge Theonella sp. J. Am. Chem. Soc. 1989;111:2582–2588. doi: 10.1021/ja00189a035. [DOI] [Google Scholar]
- 53.Kernan M.R., Molinski T.F., Faulkner D.J. Macrocyclic antifungal metabolites from the Spanish dancer nudibranch Hexa-branchus sanguineus and sponges of the genus Halichondria. J. Org. Chem. 1988;53:5014–5020. doi: 10.1021/jo00256a021. [DOI] [Google Scholar]
- 54.Nicholas G.M., Li R., MacMillan J.B., Molinski T.F. Antifungal activity of bifunctional sphingolipids. intramolecular synergism within long-chain α,ω-bis-aminoalcohols. Bioorganic Med. Chem. Lett. 2002;12:2159–2162. doi: 10.1016/S0960-894X(02)00367-0. [DOI] [PubMed] [Google Scholar]
- 55.Zhu Y., Wang Y., Gu B.-B., Yang F., Jiao W.-H., Hu G.-H., Yu H.-B., Han B.-N., Zhang W., Shen Y., et al. Antifungal bromopyrrole alkaloids from the South China Sea sponge Agelas sp. Tetrahedron. 2016;72:2964–2971. doi: 10.1016/j.tet.2016.04.020. [DOI] [Google Scholar]
- 56.Kubota T., Nakamura K., Kurimoto S.I., Sakai K., Fromont J., Gonoi T., Kobayashi J.I. Zamamidine D, a manzamine alkaloid from an Okinawan Amphimedon sp. marine sponge. J. Nat. Prod. 2017;80:1196–1199. doi: 10.1021/acs.jnatprod.6b01110. [DOI] [PubMed] [Google Scholar]
- 57.Gunasekera S.P., Pomponi S.A., McCarthy P.J. Discobahamins A and B, New Peptides from the Bahamian Deep Water Marine Sponge Discodermia sp. J. Nat. Prod. 1994;57:79–83. doi: 10.1021/np50103a011. [DOI] [PubMed] [Google Scholar]
- 58.Said A.A.E., Mahmoud B.K., Attia E.Z., Abdelmohsen U.R., Fouad M.A. Bioactive natural products from marine sponges belonging to family Hymedesmiidae. RSC Adv. 2021;11:16179–16191. doi: 10.1039/D1RA00228G. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Tripathi S.K., Feng Q., Liu L., Levin D.E., Roy K.K., Doerksen R.J., Baerson S.R., Shi X., Pan X., Xu W.-H., et al. Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway. Msphere. 2020;5 doi: 10.1128/mSphere.00818-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Jang J.-H., van Soest R.W.M., Fusetani N., Matsunaga S. Pseudoceratins A (Ia) and B (Ib), Antifungal Bicyclic Bromotyrosine-Derived Metabolites from the Marine Sponge Pseudoceratina purpurea. Cheminform. 2007;38 doi: 10.1002/chin.200727169. [DOI] [PubMed] [Google Scholar]
- 61.Chen M., Yan Y., Ge H., Jiao W.H., Zhang Z., Lin H.W. Pseudoceroximes A–E and Pseudocerolides A–E, Bromotyrosine Derivatives from a Pseudoceratina sp. Marine Sponge Collected in the South China Sea. Eur. J. Org. Chem. 2020;17:2583–2591. doi: 10.1002/ejoc.202000242. [DOI] [Google Scholar]
- 62.Shin J., Lee H.S., Kim J.Y., Shin H.J., Ahn J.W., Paul V.J. New Macrolides from the Sponge Chondrosia c orticata. J. Nat. Prod. 2004;67:1889–1892. doi: 10.1021/np040124f. [DOI] [PubMed] [Google Scholar]
- 63.Nabeta H.W., Kouokam J.C., Lasnik A.B., Fuqua J.L., Palmer K.E. Novel Antifungal Activity of Q-Griffithsin, a Broad-Spectrum Antiviral Lectin. Microbiol. Spectr. 2021;9:e0095721. doi: 10.1128/Spectrum.00957-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Nabeta H.W., Lasnik A.B., Fuqua J.L., Wang L., Rohan L.C., Palmer K.E. Antiviral lectin Q-Griffithsin suppresses fungal infection in murine models of vaginal candidiasis. Front. Cell. Infect. Microbiol. 2022;12:976033. doi: 10.3389/fcimb.2022.976033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Ganeshkumar A., Suvaithenamudhan S., Elanthamilan E., Arun G., Dileepan G.A.B., Prabhusaran N., Rajaram R. New insight of red seaweed derived Callophycin A as an alternative strategy to treat drug resistance vaginal candidiasis. Bioorganic Chem. 2020;104:104256. doi: 10.1016/j.bioorg.2020.104256. [DOI] [PubMed] [Google Scholar]
- 66.Ji N.Y., Li X.M., Li K., Ding L.P., Gloer J.B., Wang B.G. Diterpenes, sesquiterpenes, and a C15-acetogenin from the marine red alga Laurencia mariannensis. J. Nat. Prod. 2007;70:1901–1905. doi: 10.1021/np070378b. [DOI] [PubMed] [Google Scholar]
- 67.Ganesan R. Recovery of Aliphatic Fatty Acids from Red Seaweed Champia parvula (C. Agardh) and Its Antifungal Action. J. Aquat. Food Prod. Technol. 2019;28:922–932. [Google Scholar]
- 68.Feng M.-T., Yu X.-Q., Yang P., Yang H., Lin K., Mao S.-C. Two New Antifungal Polyunsaturated Fatty Acid Ethyl Esters from the Red Alga Laurencia okamurai. Chem. Nat. Compd. 2015;51:418–422. doi: 10.1007/s10600-015-1306-8. [DOI] [Google Scholar]
- 69.Greff S., Zubia M., Genta-Jouve G., Massi L., Perez T., Thomas O.P. Mahorones, highly brominated cyclopentenones from the red alga Asparagopsis taxiformis. J. Nat. Prod. 2014;77:1150–1155. doi: 10.1021/np401094h. [DOI] [PubMed] [Google Scholar]
- 70.Yu X.-Q., He W.-F., Liu D.-Q., Feng M.-T., Fang Y., Wang B., Feng L.-H., Guo Y.-W., Mao S.-C. A seco -laurane sesquiterpene and related laurane derivatives from the red alga Laurencia okamurai Yamada. Phytochemistry. 2014;103:162–170. doi: 10.1016/j.phytochem.2014.03.021. [DOI] [PubMed] [Google Scholar]
- 71.Lopes G., Pinto E., Andrade P.B., Valentao P. Antifungal activity of phlorotannins against dermatophytes and yeasts: Ap-proaches to the mechanism of action and influence on Candida albicans virulence factor. PLoS ONE. 2013;8:e72203. doi: 10.1371/journal.pone.0072203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Liu A.-H., Liu D.-Q., Liang T.-J., Yu X.-Q., Feng M.-T., Yao L.-G., Fang Y., Wang B., Feng L.-H., Zhang M.-X., et al. Caulerprenylols A and B, two rare antifungal prenylated para-xylenes from the green alga Caulerpa racemosa. Bioorganic Med. Chem. Lett. 2013;23:2491–2494. doi: 10.1016/j.bmcl.2013.03.038. [DOI] [PubMed] [Google Scholar]
- 73.Lin A.S., Stout E.P., Prudhomme J., Roch K.L., Fairchild C.R., Franzblau S.G., Kubanek J. Bioactive Bromophycolides R− U from the Fijian red alga Callophycus serratus. J. Nat. Prod. 2010;73:275–278. doi: 10.1021/np900686w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Alarif W.M., Al-Lihaibi S.S., Ayyad S.-E.N., Abdel-Rhman M.H., Badria F.A. Laurene-type sesquiterpenes from the Red Sea red alga Laurencia obtusa as potential antitumor–antimicrobial agents. Eur. J. Med. Chem. 2012;55:462–466. doi: 10.1016/j.ejmech.2012.06.060. [DOI] [PubMed] [Google Scholar]
- 75.Xu X., Piggott A.M., Yin L., Capon R.J., Song F. Symphyocladins A–G: Bromophenol adducts from a Chinese marine red alga, Symphyocladia latiuscula. Tetrahedron Lett. 2012;53:2103–2106. doi: 10.1016/j.tetlet.2012.02.044. [DOI] [Google Scholar]
- 76.Oh K.-B., Lee J.H., Chung S.-C., Shin J., Shin H.J., Kim H.-K., Lee H.-S. Antimicrobial activities of the bromophenols from the red alga Odonthalia corymbifera and some synthetic derivatives. Bioorganic Med. Chem. Lett. 2008;18:104–108. doi: 10.1016/j.bmcl.2007.11.003. [DOI] [PubMed] [Google Scholar]
- 77.Li X.C., Jacob M.R., Ding Y., Agarwal A.K., Smillie T.J., Khan S.I., Clark A.M. Capisterones A and B, which enhance fluconazole activity in Saccharomyces cerevisiae, from the marine green alga Penicillus capitatus. J. Nat. Prod. 2006;69:542–546. doi: 10.1021/np050396y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Ankisetty S., Nandiraju S., Win H., Park Y.C., Amsler C.D., McClintock J.B., Baker J.A., Diyabalanage T.K., Pasaribu A., Singh M.P., et al. Chemical Investigation of Predator-Deterred Macroalgae from the Antarctic Peninsula. J. Nat. Prod. 2004;67:1295–1302. doi: 10.1021/np049965c. [DOI] [PubMed] [Google Scholar]
- 79.Yang W.-S., Qi X.-R., Xu Q.-Z., Yuan C.-H., Yi Y.-H., Tang H.-F., Shen L., Han H. A new sulfated triterpene glycoside from the sea cucumber Colochirus quadrangularis, and evaluation of its antifungal, antitumor and immunomodulatory activities. Bioorganic Med. Chem. 2021;41:116188. doi: 10.1016/j.bmc.2021.116188. [DOI] [PubMed] [Google Scholar]
- 80.Elbandy M., Rho J.R., Afifi R. Analysis of saponins as bioactive zoochemicals from the marine functional food sea cucumber Bohadschia cousteaui. Eur. Food Res. Technol. 2014;238:937–955. doi: 10.1007/s00217-014-2171-6. [DOI] [Google Scholar]
- 81.Wang X.-H., Zou Z.-R., Yi Y.-H., Han H., Li L., Pan M.-X. Variegatusides: New Non-Sulphated Triterpene Glycosides from the Sea Cucumber Stichopus variegates Semper. Mar. Drugs. 2014;12:2004–2018. doi: 10.3390/md12042004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Wang Z., Zhang H., Yuan W., Gong W., Tang H., Liu B., Krohn K., Li L., Yi Y., Zhang W. Antifungal nortriterpene and triterpene glycosides from the sea cucumber Apostichopus japonicus Selenka. Food Chem. 2012;132:295–300. doi: 10.1016/j.foodchem.2011.10.080. [DOI] [PubMed] [Google Scholar]
- 83.Yuan W.-H., Yi Y.-H., Tan R.-X., Wang Z.-L., Sun G.-Q., Xue M., Zhang H.-W., Tang H.-F. Antifungal Triterpene Glycosides from the Sea Cucumber Holothuria (Microthele) axiloga. Planta Medica. 2009;75:647–653. doi: 10.1055/s-0029-1185381. [DOI] [PubMed] [Google Scholar]
- 84.Yuan W.-H., Yi Y.-H., Tang H.-F., Liu B.-S., Wang Z.-L., Sun G.-Q., Zhang W., Li L., Sun P. Antifungal Triterpene Glycosides from the Sea Cucumber Bohadschia marmorata. Planta Medica. 2008;75:168–173. doi: 10.1055/s-0028-1088348. [DOI] [PubMed] [Google Scholar]
- 85.Yuan W.-H., Yi Y.-H., Xue M., Zhang H.-W., LA M.-P. Two Antifungal Active Triterpene Glycosides from Sea Cucumber Holothuria (Microthele) axiloga. Chin. J. Nat. Med. 2008;6:105–108. doi: 10.3724/SP.J.1009.2008.00105. [DOI] [Google Scholar]
- 86.Kumar R., Chaturvedi A.K., Shukla P.K., Lakshmi V. Antifungal activity in triterpene glycosides from the sea cucumber Actinopyga lecanora. Bioorganic Med. Chem. Lett. 2007;17:4387–4391. doi: 10.1016/j.bmcl.2006.12.052. [DOI] [PubMed] [Google Scholar]
- 87.Hagström A., Pommier T., Rohwer F., Simu K., Stolte W., Svensson D., Zweifel U.L. Use of 16S Ribosomal DNA for Delineation of Marine Bacterioplankton Species. Appl. Environ. Microbiol. 2002;68:3628–3633. doi: 10.1128/AEM.68.7.3628-3633.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Debbab A., Aly A.H., Lin W.H., Proksch P. Bioactive Compounds from Marine Bacteria and Fungi. Microb. Biotechnol. 2010;3:544–563. doi: 10.1111/j.1751-7915.2010.00179.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Dhakal D., Pokhrel A.R., Shrestha B., Maharjan J., Sohng J.K. Streptomyces species: A promising source of antifungal metabolites. Appl. Microbiol. Biotechnol. 2020;104:2253–2264. [Google Scholar]
- 90.Solanki R., Khanna M., Lal R. Bioactive compounds from marine actinomycetes. Indian J. Microbiol. 2008;48:410–431. doi: 10.1007/s12088-008-0052-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.El-Tarabily K.A., Nassar A.H., Sivasithamparam K. Microbial Metabolites in Sustainable Agroecosystem. Springer; Singapore: 2020. Soil Actinomycetes and Their Metabolites for Control of Plant Fungal Pathogens; pp. 279–310. [Google Scholar]
- 92.Bao Y., Li H., Dong Y., Duan H., Li H., Li W. Genome-Guided Discovery of Antifungal Filipins from a Deep-Sea-Derived Streptomyces antibioticus. J. Nat. Prod. 2022;85:365–374. doi: 10.1021/acs.jnatprod.1c00952. [DOI] [PubMed] [Google Scholar]
- 93.Li W., Ding L., Li J., Wen H., Liu Y., Tan S., Yan X., Shi Y., Lin W., Lin H.-W., et al. Novel Antimycin Analogues with Agricultural Antifungal Activities from the Sponge-Associated Actinomycete Streptomyces sp. NBU3104. J. Agric. Food Chem. 2022;70:8309–8316. doi: 10.1021/acs.jafc.2c02626. [DOI] [PubMed] [Google Scholar]
- 94.Zhang Z., Zhou T., Harunari E., Oku N., Igarashi Y. Iseolides A–C, antifungal macrolides from a coral-derived actinomycete of the genus Streptomyces. J. Antibiot. 2020;73:534–541. doi: 10.1038/s41429-020-0304-7. [DOI] [PubMed] [Google Scholar]
- 95.Zhang S., Gui C., Shao M., Kumar P.S., Huang H., Ju J. Antimicrobial tunicamycin derivatives from the deep sea-derived Streptomyces xinghaiensis SCSIO S15077. Nat. Prod. Res. 2018;34:1499–1504. doi: 10.1080/14786419.2018.1493736. [DOI] [PubMed] [Google Scholar]
- 96.Harunari E., Imada C., Igarashi Y. Konamycins A and B and Rubromycins CA1 and CA2, Aromatic Polyketides from the Tunicate-Derived Streptomyces hyaluromycini MB-PO13T. J. Nat. Prod. 2019;82:1609–1615. doi: 10.1021/acs.jnatprod.9b00107. [DOI] [PubMed] [Google Scholar]
- 97.Pérez-Victoria I., Oves-Costales D., Lacret R., Martín J., Sánchez-Hidalgo M., Díaz C., Reyes F. Structure elucidation and biosynthetic gene cluster analysis of caniferolides A–D, new bioactive 36-membered macrolides from the marine-derived Streptomyces caniferus CA-271066. Org. Biomol. Chem. 2019;17:2954–2971. doi: 10.1039/C8OB03115K. [DOI] [PubMed] [Google Scholar]
- 98.Pan J.M., Chen H.Q., Wang H., Yang L., Cai C.H., Mi C.N., Mei W.L. New antifungal cycloheximide epimers pro-duced by Streptomyces sp. YG7. J. Asian Nat. Prod. Res. 2019;23:110–116. doi: 10.1080/10286020.2019.1706499. [DOI] [PubMed] [Google Scholar]
- 99.Zhou B., Huang Y., Zhang H.-J., Li J.-Q., Ding W.-J. Nitricquinomycins A-C, uncommon naphthopyrrolediones from the Streptomyces sp. ZS-A45. Tetrahedron. 2019;75:3958–3961. doi: 10.1016/j.tet.2019.05.060. [DOI] [Google Scholar]
- 100.Chen M., Chai W., Zhu R., Song T., Zhang Z., Lian X.-Y. Streptopyrazinones A−D, rare metabolites from marine-derived Streptomyces sp. ZZ446. Tetrahedron. 2018;74:2100–2106. doi: 10.1016/j.tet.2018.03.028. [DOI] [Google Scholar]
- 101.Jiang Y.-J., Zhang D.-S., Zhang H.-J., Li J.-Q., Ding W.-J., Xu C.-D., Ma Z.-J. Medermycin-Type Naphthoquinones from the Marine-Derived Streptomyces sp. XMA39. J. Nat. Prod. 2018;81:2120–2124. doi: 10.1021/acs.jnatprod.8b00544. [DOI] [PubMed] [Google Scholar]
- 102.Wang F., Fu S.N., Bao Y.X., Yang Y., Shen H.F., Lin B.R., Zhou G.X. Kitamycin C, a new antimycin-type antibiotic from Streptomyces antibioticus strain 200-09. Nat. Prod. Res. 2017;31:1819–1824. doi: 10.1080/14786419.2017.1295240. [DOI] [PubMed] [Google Scholar]
- 103.Aksoy S., Uzel A., Bedir E. Cytosine-type nucleosides from marine-derived Streptomyces rochei 06CM016. J. Antibiot. 2015;69:51–56. doi: 10.1038/ja.2015.72. [DOI] [PubMed] [Google Scholar]
- 104.Bae M., Kim H., Moon K., Nam S.J., Shin J., Oh K.B., Oh D.C. Mohangamides A and B, new dilactone-tethered pseu-do-dimeric peptides inhibiting Candida albicans isocitrate lyase. Org. Lett. 2015;17:712–715. doi: 10.1021/ol5037248. [DOI] [PubMed] [Google Scholar]
- 105.Che Q., Li T., Liu X., Yao T., Li J., Gu Q., Li D., Li W., Zhu T. Genome scanning inspired isolation of reedsmycins A–F, poly-ene-polyol macrolides from Streptomyces sp. CHQ-64. Rsc Adv. 2015;5:22777–22782. doi: 10.1039/C4RA15415K. [DOI] [Google Scholar]
- 106.Lacret R., Oves-Costales D., Gómez C., Díaz C., De la Cruz M., Pérez-Victoria I., Vicente F., Genilloud O., Reyes F. New ikarugamycin deriv-atives with antifungal and antibacterial properties from Streptomyces zhaozhouensis. Mar. Drugs. 2014;13:128–140. doi: 10.3390/md13010128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Ambavane V., Tokdar P., Parab R., Sreekumar E.S., Mahajan G., Mishra P.D., D’souza L., Ranadive P. Caerulomycin A—An Antifungal Compound Isolated from Marine Actinomycetes. Adv. Microbiol. 2014;4:567–578. doi: 10.4236/aim.2014.49063. [DOI] [Google Scholar]
- 108.Moon K., Ahn C.-H., Shin Y., Won T.H., Ko K., Lee S.K., Oh K.-B., Shin J., Nam S.-I., Oh D.-C. New Benzoxazine Secondary Metabolites from an Arctic Actinomycete. Mar. Drugs. 2014;12:2526–2538. doi: 10.3390/md12052526. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Kim D.G., Moon K., Kim S.H., Park S.H., Park S., Lee S.K., Oh K.B., Shin J.H., Oh D.C. Bahamaolides A and B, antifungal polyene polyol macrolides from the marine actinomycete Streptomyces sp. J. Nat. Prod. 2012;75:959–967. doi: 10.1021/np3001915. [DOI] [PubMed] [Google Scholar]
- 110.Kaneda M., Naid T., Kithara T., Nakamura S., Kitahara T., Nakamura S. Carbazomycins G and H, novel carbazomycin-congeners containing a quinol molety. J. Antibiot. 1988;45:602–608. doi: 10.7164/antibiotics.41.602. [DOI] [PubMed] [Google Scholar]
- 111.Yuan G., Hong K., Lin H., She Z., Li J. New Azalomycin F Analogs from Mangrove Streptomyces sp. 211726 with Activity against Microbes and Cancer Cells. Mar. Drugs. 2013;11:817–829. doi: 10.3390/md11030817. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Xu L.Y., Quan X.S., Wang C., Sheng H.F., Zhou G.X., Lin B.R., Jiang R.W., Yao X.S. Antimycins A 19 and A 20, two new anti-mycins produced by marine actinomycete Streptomyces antibioticus H74-18. J. Antibiot. 2011;64:661–665. doi: 10.1038/ja.2011.65. [DOI] [PubMed] [Google Scholar]
- 113.El-Gendy M.M.A., El-Bondkly A.M.A. Production and genetic improvement of a novel antimycotic agent, Saadamycin, against Dermatophytes and other clinical fungi from Endophytic Streptomyces sp. Hedaya48. J. Ind. Microbiol. Biotechnol. 2010;37:831–841. doi: 10.1007/s10295-010-0729-2. [DOI] [PubMed] [Google Scholar]
- 114.Han Y., Yang B., Zhang F., Miao X., Li Z. Characterization of Antifungal Chitinase from Marine Streptomyces sp. DA11 Associated with South China Sea Sponge Craniella Australiensis. Mar. Biotechnol. 2008;11:132–140. doi: 10.1007/s10126-008-9126-5. [DOI] [PubMed] [Google Scholar]
- 115.Hohmann C., Schneider K., Bruntner C., Irran E., Nicholson G., Bull A.T., Jones A.L., Brown R., Stach J.E.M., Goodfellow M., et al. Caboxamycin, a new antibiotic of the benzoxazole family produced by the deep-sea strain Streptomyces sp. NTK 937. J. Antibiot. 2009;62:99–104. doi: 10.1038/ja.2008.24. [DOI] [PubMed] [Google Scholar]
- 116.Shaaban K., Shaaban M., Facey P., Fotso S., Frauendorf H., Helmke E., Maier A., Fiebig H.H., Laatsch H. Electrospray Ionization Mass Spectra of Piperazimycins A and B and γ-Butyrolactones from a Marine-derived Streptomyces sp. J. Antibiot. 2008;61:736–746. doi: 10.1038/ja.2008.87. [DOI] [PubMed] [Google Scholar]
- 117.Zhang F., Zhao M., Braun D.R., Ericksen S.S., Piotrowski J.S., Nelson J., Peng J., Ananiev G.E., Chanana S., Barns K., et al. A marine microbiome antifungal targets urgent-threat drug-resistant fungi. Science. 2020;370:974–978. doi: 10.1126/science.abd6919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Peltola M., Tauraite D., Kananen E. Antifungal compounds from Streptomyces hygroscopicus and their synergistic effects with fluconazole. J. Antibiot. 2020;73:831–839. [Google Scholar]
- 119.Li Z., Li J., Li Y., Li Y., Zhao L.X. Production of Antifungal Metabolites by Streptomyces sp. Isolated from the Soil of Mawei Mountain. J. Agric. Sci. 2021;13:96–102. [Google Scholar]
- 120.Malla M.A., Dubey A.K., Kumar A., Yadav P. Streptomyces as a source of antifungal metabolites: A review. J. Appl. Microbiol. 2021;131:1549–1560. [Google Scholar]
- 121.Chen S., Zhang D., Chen M., Zhang Z., Lian X.-Y. A rare diketopiperazine glycoside from marine-sourced Streptomyces sp. ZZ446. Nat. Prod. Res. 2018;34:1046–1050. doi: 10.1080/14786419.2018.1544978. [DOI] [PubMed] [Google Scholar]
- 122.Kumar A., Sørensen J.L., Hansen F.T., Arvas M., Syed M.F., Hassan L., Benz J.P., Record E., Henrissat B., Pöggeler S., et al. Genome Sequencing and analyses of Two Marine Fungi from the North Sea Unraveled a Plethora of Novel Biosynthetic Gene Clusters. Sci. Rep. 2018;8:10187. doi: 10.1038/s41598-018-28473-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Setiyono E., Adhiwibawa M.A.S., Indrawati R., Prihastyanti M.N.U., Shioi Y., Brotosudarmo T.H.P. An Indonesian Marine Bacterium, Pseudoalteromonas rubra, Produces Antimicrobial Prodiginine Pigments. ACS Omega. 2020;5:4626–4635. doi: 10.1021/acsomega.9b04322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.Karim M.R.U., Harunari E., Oku N., Akasaka K., Igarashi Y. Bulbimidazoles A–C, Antimicrobial and Cytotoxic Alkanoyl Imidazoles from a Marine Gammaproteobacterium Microbulbifer Species. J. Nat. Prod. 2020;83:1295–1299. doi: 10.1021/acs.jnatprod.0c00082. [DOI] [PubMed] [Google Scholar]
- 125.Anjum K., Kaleem S., Yi W., Zheng G., Lian X., Zhang Z. Novel antimicrobial indolepyrazines A and B from the ma-rine-associated Acinetobacter sp. ZZ1275. Mar. Drugs. 2019;17:89. doi: 10.3390/md17020089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Anjum K., Sadiq I., Chen L., Kaleem S., Li X.-C., Zhang Z., Lian X.-Y. Novel antifungal janthinopolyenemycins A and B from a co-culture of marine-associated Janthinobacterium spp. ZZ145 and ZZ148. Tetrahedron Lett. 2018;59:3490–3494. doi: 10.1016/j.tetlet.2018.08.022. [DOI] [Google Scholar]
- 127.Tareq F.S., Lee H.S., Lee Y.J., Lee J.S., Shin H.J. Ieodoglucomide C and ieodoglycolipid, new glycolipids from a ma-rine-derived bacterium Bacillus licheniformis 09IDYM23. Lipids. 2015;50:513–519. doi: 10.1007/s11745-015-4014-z. [DOI] [PubMed] [Google Scholar]
- 128.Wyche T.P., Piotrowski J.S., Hou Y., Braun D., Deshpande R., McIlwain S., Ong I.M., Myers C.L., Guzei I.A., Westler W.M., et al. Forazoline A: Marine-Derived Polyketide with Antifungal In Vivo Efficacy. Angew. Chem. Int. Ed. 2014;53:11583–11586. doi: 10.1002/anie.201405990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Tareq F.S., Kim J.H., Lee M.A., Lee H.-S., Lee J.-S., Lee Y.-J., Shin H.J. Antimicrobial Gageomacrolactins Characterized from the Fermentation of the Marine-Derived Bacterium Bacillus subtilis under Optimum Growth Conditions. J. Agric. Food Chem. 2013;61:3428–3434. doi: 10.1021/jf4009229. [DOI] [PubMed] [Google Scholar]
- 130.Xu Z., Zhang Y., Fu H., Zhong H., Hong K., Zhu W. Antifungal quinazolinones from marine-derived Bacillus cereus and their preparation. Bioorganic Med. Chem. Lett. 2011;21:4005–4007. doi: 10.1016/j.bmcl.2011.05.002. [DOI] [PubMed] [Google Scholar]
- 131.Kunze B., Böhlendorf B., Reichenbach H., Höfle G. Pedein A and B: Production, Isolation, Structure Elucidation and Biological Properties of New Antifungal Cyclopeptides from Chondromyces pediculatus (Myxobacteria) J. Antibiot. 2008;61:18–26. doi: 10.1038/ja.2008.104. [DOI] [PubMed] [Google Scholar]
- 132.Al-Zereini W., Schuhmann I., Laatsch H., Helmke E., Anke H. New Aromatic Nitro Compounds from Salegentibacter sp. T436, an Arctic Sea Ice Bacterium: Taxonomy, Fermentation, Isolation and Biological Activities. J. Antibiot. 2007;60:301–308. doi: 10.1038/ja.2007.38. [DOI] [PubMed] [Google Scholar]
- 133.Neuhof T., Schmieder P., Preussel K., Dieckmann R., Pham H., Bartl F., von Döhren H. Hassallidin A, a glycosylated lipopeptide with antifungal activity from the cyanobacterium Hassallia sp. J. Nat. Prod. 2005;68:695–700. doi: 10.1021/np049671r. [DOI] [PubMed] [Google Scholar]
- 134.Barsby T., Kelly M.T., Andersen R.J. Tupuseleiamides and Basiliskamides, New Acyldipeptides and Antifungal Polyketides Produced in Culture by a Bacilluslaterosporus Isolate Obtained from a Tropical Marine Habitat. J. Nat. Prod. 2002;65:1447–1451. doi: 10.1021/np0201321. [DOI] [PubMed] [Google Scholar]
- 135.MacMillan J.B., Ernst-Russell M.A., De Ropp J.S., Molinski T.F. Lobocyclamides A−C, Lipopeptides from a Cryptic Cyano-bacterial Mat Containing Lyngbya confervoides. J. Org. Chem. 2002;67:8210–8215. doi: 10.1021/jo0261909. [DOI] [PubMed] [Google Scholar]
- 136.Zhang K., Zhang X., Lin R., Yang H., Song F., Xu X., Wang L. New Secondary Metabolites from the Marine-Derived Fungus Talaromyces mangshanicus BTBU20211089. Mar. Drugs. 2022;20:79. doi: 10.3390/md20020079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.Ningsih B.N.S., Rukachaisirikul V., Phongpaichit S., Preedanon S., Sakayaroj J., Muanprasat C. A nonadride derivative from the marine-derived fungus Aspergillus chevalieri PSU-AMF79. Nat. Prod. Res. 2022;37:2311–2318. doi: 10.1080/14786419.2022.2039651. [DOI] [PubMed] [Google Scholar]
- 138.Nuansri S., Rukachaisirikul V., Rungwirain N., Kaewin S., Yimnual C., Phongpaichit S., Preedanon S., Sakayaroj J., Muanprasat C. α-Pyrone and decalin derivatives from the marine-derived fungus Trichoderma harzianum PSU-MF79. Nat. Prod. Res. 2021;36:5462–5469. doi: 10.1080/14786419.2021.2015593. [DOI] [PubMed] [Google Scholar]
- 139.Ma M., Yi W., Qin L., Lian X.-Y., Zhang Z. Talaromydien a and talaroisocoumarin A, new metabolites from the marine-sourced fungus Talaromyces sp. ZZ1616. Nat. Prod. Res. 2020;36:460–465. doi: 10.1080/14786419.2020.1779265. [DOI] [PubMed] [Google Scholar]
- 140.Wu J.-S., Shi X.-H., Yao G.-S., Shao C.-L., Fu X.-M., Zhang X.-L., Guan H.-S., Wang C.-Y. New Thiodiketopiperazine and 3,4-Dihydroisocoumarin Derivatives from the Marine-Derived Fungus Aspergillus terreus. Mar. Drugs. 2020;18:132. doi: 10.3390/md18030132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.Yamazaki H., Takahashi O., Kirikoshi R., Yagi A., Ogasawara T., Bunya Y., Namikoshi M. Epipolythiodiketopipera-zine and trichothecene derivatives from the NaI-containing fermentation of marine-derived Trichoderma cf. brevicompactum. J. Antibiot. 2020;73:559–567. doi: 10.1038/s41429-020-0314-5. [DOI] [PubMed] [Google Scholar]
- 142.Yang B., He Y., Lin S., Zhang J., Li H., Wang J., Zhang Y. Antimicrobial dolabellanes and atranones from a ma-rine-derived strain of the toxigenic fungus Stachybotrys chartarum. J. Nat. Prod. 2019;82:1923–1929. doi: 10.1021/acs.jnatprod.9b00305. [DOI] [PubMed] [Google Scholar]
- 143.Shaala L.A., Youssef D.T. Identification and bioactivity of compounds from the fungus Penicillium sp. CYE-87 isolated from a marine tunicate. Mar. Drugs. 2015;13:1698–1709. doi: 10.3390/md13041698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 144.Ding L., Xu P., Li T., Liao X., He S., Xu S. Asperfurandiones A and B, two antifungal furandione analogs from a ma-rine-derived fungus Aspergillus versicolor. Nat. Prod. Res. 2019;33:3404–3408. doi: 10.1080/14786419.2018.1480622. [DOI] [PubMed] [Google Scholar]
- 145.Huang Z.-H., Nong X.-H., Liang X., Qi S.-H. New tetramic acid derivatives from the deep-sea-derived fungus Cladosporium sp. SCSIO z0025. Tetrahedron. 2018;74:2620–2626. doi: 10.1016/j.tet.2018.04.010. [DOI] [Google Scholar]
- 146.Yu H.-B., Wang X.-L., Xu W.-H., Zhang Y.-X., Qian Y.-S., Zhang J.-P., Lu X.-L., Liu X.-Y. Eutypellenoids A–C, New Pimarane Diterpenes from the Arctic Fungus Eutypella sp. D-1. Mar. Drugs. 2018;16:284. doi: 10.3390/md16080284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Song T., Chen M., Chai W., Zhang Z., Lian X.Y. New bioactive pyrrospirones C− I from a marine-derived fungus Penicillium sp. ZZ380. Tetrahedron. 2018;74:884–891. doi: 10.1016/j.tet.2018.01.015. [DOI] [Google Scholar]
- 148.Zhang Y., Li X.M., Wang B.G. Nigerasperones A~C, new monomeric and dimeric naphtho-γ-pyrones from a marine al-ga-derived endophytic fungus Aspergillus niger EN-13. J. Antibiot. 2007;60:204–210. doi: 10.1038/ja.2007.24. [DOI] [PubMed] [Google Scholar]
- 149.Wang J., Yao Q.-F., Amin M., Nong X.-H., Zhang X.-Y., Qi S.-H. Penicillenols from a deep-sea fungus Aspergillus restrictus inhibit Candida albicans biofilm formation and hyphal growth. J. Antibiot. 2017;70:763–770. doi: 10.1038/ja.2017.45. [DOI] [PubMed] [Google Scholar]
- 150.Okabe M., Sugita T., Kinoshita K., Koyama K. Macrolides from a Marine-Derived Fungus, Penicillium meleagrinum var. viridiflavum, Showing Synergistic Effects with Fluconazole against Azole-Resistant Candida albicans. J. Nat. Prod. 2016;79:1208–1212. doi: 10.1021/acs.jnatprod.6b00019. [DOI] [PubMed] [Google Scholar]
- 151.Chen C.J., Zhou Y.Q., Liu X.X., Zhang W.J., Hu S.S., Lin L.P., Ge H.M. Antimicrobial and anti-inflammatory com-pounds from a marine fungus Pleosporales sp. Tetrahedron Lett. 2015;56:6183–6189. doi: 10.1016/j.tetlet.2015.09.079. [DOI] [Google Scholar]
- 152.Xu D.X., Sun P., Kurtan T., Mandi A., Tang H., Liu B., Zhang W. Polyhydroxy cyclohexanols from a Dendrodochium sp. fungus associated with the sea cucumber Holothuria nobilis Selenka. J. Nat. Prod. 2014;77:1179–1184. doi: 10.1021/np500024r. [DOI] [PubMed] [Google Scholar]
- 153.Haga A., Tamoto H., Ishino M., Kimura E., Sugita T., Kinoshita K., Koyama K. Pyridone alkaloids from a ma-rine-derived fungus, Stagonosporopsis cucurbitacearum, and their activities against azole-resistant Candida albicans. J. Nat. Prod. 2013;76:750–754. doi: 10.1021/np300876t. [DOI] [PubMed] [Google Scholar]
- 154.Singh S.B., Zink D.L., Doss G.A., Polishook J.D., Ruby C., Register E., Kelly T.M., Bonfiglio C., Williamson J.M., Kelly R. Citrafungins A and B, Two New Fungal Metabolite Inhibitors of GGTase I with Antifungal Activity. Org. Lett. 2004;6:337–340. doi: 10.1021/ol0361249. [DOI] [PubMed] [Google Scholar]
- 155.Shigemori H., Kasai Y., Komatsu K., Tsuda M., Mikami Y., Kobayashi J. Sporiolides A and B, New Cytotoxic Twelve-Membered Macrolides from a Marine-Derived Fungus Cladosporium Species. Mar. Drugs. 2004;2:164–169. doi: 10.3390/md204164. [DOI] [Google Scholar]
- 156.Edrada R.A., Heubes M., Brauers G., Wray V., Berg A., Gräfe U., Wohlfarth M., Mühlbacher J., Schaumann K., Bring-mann G., et al. Online analysis of xestodecalactones A-C, novel bioactive metabolites from the fungus Penicillium cf montanense and their subsequent isolation from the sponge Xestospongia exigua. J. Nat. Prod. 2002;65:1598–1604. doi: 10.1021/np020085c. [DOI] [PubMed] [Google Scholar]
- 157.Toghueo R.M.K., Boyom F.F. Endophytic Penicillium species and their agricultural, biotechnological, and pharmaceutical applications. 3 Biotech. 2020;10:107. doi: 10.1007/s13205-020-2081-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 158.Khan I., Zhang H., Liu W., Zhang L., Peng F., Chen Y., Zhang Q., Zhang G., Zhang W., Zhang C. Identification and bioactivity evaluation of secondary metabolites from Antarctic-derived Penicillium chrysogenum CCTCC M 2020019. RSC Adv. 2020;10:20738–20744. doi: 10.1039/D0RA03529G. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 159.Ding Z., Zhou H., Wang X., Huang H., Wang H., Zhang R., Wang Z., Han J. Deletion of the Histone Deacetylase HdaA in Endophytic Fungus Penicillium chrysogenum Fes1701 Induces the Complex Response of Multiple Bioactive Secondary Metabolite Production and Relevant Gene Cluster Expression. Molecules. 2020;25:3657. doi: 10.3390/molecules25163657. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 160.Bhatnagar I., Kim S.-K. Immense Essence of Excellence: Marine Microbial Bioactive Compounds. Mar. Drugs. 2010;8:2673–2701. doi: 10.3390/md8102673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 161.Kaleem S., Qin L., Yi W., Lian X.-Y., Zhang Z. Bioactive Metabolites from the Mariana Trench Sediment-Derived Fungus Penicillium sp. SY2107. Mar. Drugs. 2020;18:258. doi: 10.3390/md18050258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 162.Shaala L.A., Alzughaibi T., Genta-Jouve G., Youssef D.T.A. Fusaripyridines A and B. Highly Oxygenated Antimicrobial Alkaloid Dimers Featuring an Unprecedented 1,4-Bis(2-hydroxy-1,2-dihydropyridin-2-yl)butane-2,3-dione Core from the Marine Fungus Fusarium sp. LY019. Mar. Drugs. 2021;19:505. doi: 10.3390/md19090505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.Hua Y., Pan R., Bai X., Wei B., Chen J., Wang H., Zhang H. Aromatic Polyketides from a Symbiotic Strain Aspergillus fumigatus D and Characterization of Their Biosynthetic Gene D8.t287. Mar. Drugs. 2020;18:324. doi: 10.3390/md18060324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 164.Karim M.R.U., Harunari E., Sharma A.R., Oku N., Akasaka K., Urabe D., Igarashi Y. Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: Application of 1JC, H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial me-tabolites. Beilstein. J. Org. Chem. 2020;16:2719–2727. doi: 10.3762/bjoc.16.222. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 165.Pérez M., Schleissner C., Fernández R., Rodríguez P., Reyes F., Zuñiga P., de la Calle F., Cuevas C. PM100117 and PM100118, new antitumor macrolides produced by a marine Streptomyces caniferus GUA-06-05-006A. J. Antibiot. 2015;69:388–394. doi: 10.1038/ja.2015.121. [DOI] [PubMed] [Google Scholar]
- 166.Nuzzo G., Cutignano A., Sardo A., Fontana A. Antifungal Amphidinol 18 and Its 7-Sulfate Derivative from the Marine Dinoflagellate Amphidinium carterae. J. Nat. Prod. 2014;77:1524–1527. doi: 10.1021/np500275x. [DOI] [PubMed] [Google Scholar]
- 167.Shaala L.A., Youssef D.T., Ibrahim S.R., Mohamed G.A., Badr J.M., Risinger A.L., Mooberry S.L. Didemnaketals F and G, new bioactive spiroketals from a Red Sea ascidian Didemnum species. Mar. Drugs. 2014;12:5021–5034. doi: 10.3390/md12095021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 168.López-Abarrategui C., Alba A., Silva O.N., Reyes-Acosta O., Vasconcelos I.M., Oliveira J.T., Migliolo L., Costa M.P., Costa C.R., Silva M.R., et al. Functional characterization of a synthetic hydrophilic antifungal peptide derived from the marine snail Cenchritis muricatus. Biochimie. 2012;94:968–974. doi: 10.1016/j.biochi.2011.12.016. [DOI] [PubMed] [Google Scholar]
- 169.Fedders H., Michalek M., Grötzinger J., Leippe M. An exceptional salt-tolerant antimicrobial peptide derived from a novel gene family of haemocytes of the marine invertebrate Ciona intestinalis. Biochem. J. 2008;416:65–75. doi: 10.1042/BJ20080398. [DOI] [PubMed] [Google Scholar]
- 170.Jang W.S., Kim H.K., Lee K.Y., Kim S.A., Han Y.S., Lee I.H. Antifungal activity of synthetic peptide derived from halocidin, antimicrobial peptide from the tunicate, Halocynthia aurantium. FEBS Lett. 2006;580:1490–1496. doi: 10.1016/j.febslet.2006.01.041. [DOI] [PubMed] [Google Scholar]
- 171.Kossuga M.H., MacMillan J.B., Rogers E.W., Molinski T.F., Nascimento G.G., Rocha R.M., Berlinck R.G. (2S,3R)-2-aminododecan-3-ol, a new antifungal agent from the Ascidian Clavelina Oblonga. J. Nat. Prod. 2004;67:1879–1881. doi: 10.1021/np049782q. [DOI] [PubMed] [Google Scholar]
- 172.Schupp P., Poehner T., Edrada R., Ebel R., Berg A., Wray V., Proksch P. Eudistomins W and X, two new β-carbolines from the micronesian tunicate Eudistoma sp. J. Nat. Prod. 2003;66:272–275. doi: 10.1021/np020315n. [DOI] [PubMed] [Google Scholar]
- 173.Alves A.M.C.V., Cruz-Martins N., Rodrigues C.F. Marine Compounds with Anti-Candida sp. Activity: A Promised “Land” for New Antifungals. J. Fungi. 2022;8:669. doi: 10.3390/jof8070669. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data is contained within the article.