Antifungal and Antibacterial Activities of Isolated Marine Compounds

To combat the ineffectiveness of currently available pharmaceutical medications, caused by the emergence of increasingly resistant bacterial and fungal strains, novel antibacterial and antifungal medications are urgently needed. Novel natural compounds with antimicrobial activities can be obtained by exploring underexplored habitats such as the world’s oceans. The oceans represent the largest ecosystem on earth, with a high diversity of organisms. Oceans have received some attention in the past few years, and promising compounds with antimicrobial activities were isolated from marine organisms such as bacteria, fungi, algae, sea cucumbers, sea sponges, etc. This review covers 56 antifungal and 40 antibacterial compounds from marine organisms. These compounds are categorized according to their chemical structure groups, including polyketides, alkaloids, ribosomal peptides, and terpenes, and their organismal origin. The review provides the minimum inhibitory concentration MIC values and the bacterial/fungal strains against which these chemical compounds show activity. This study shows strong potential for witnessing the development of new novel antimicrobial drugs from these natural compounds isolated and evaluated for their antimicrobial activities.


Introduction
Antibiotics are one of the most powerful medications developed to fight against dangerous infections. Their discovery has greatly improved human and animal health. Unfortunately, we are now witnessing a period in which people are dying from untreatable infections. The particular reason for these circumstances is the emergence and spread of antibiotic-resistant microorganisms. Antibiotic-resistant infections can be difficult, and sometimes impossible, to treat, resulting in mortality cases. The center for disease control and prevention CDC's 2019 Antibiotic Resistance (AR) Threats Report mentions that antimicrobial resistance is an urgent global public health threat, killing at least 1.27 million people worldwide [1]. The report adds that more than 2.8 million antimicrobial-resistant infections occur each year in the U.S.A., causing the death of more than 35,000 people. Scheme 1. Chemical structures of cited compounds that were isolated from marine organisms and that showed antimicrobial activities. Scheme 1. Chemical structures of cited compounds that were isolated from marine organisms and that showed antimicrobial activities.
Actinomycetes were used to create the new and superior antifungal drug caerulomycin A. (5 in Scheme 1). Actinomycete strain PM0525875 for extraction was obtained from a marine invertebrate. Actinomycetes extracts showed strong effectiveness against drugresistant fungus strains in in vitro investigations. The fluconazole-resistant Candida glabrata, C. albicans, C. albicans CO9, and Candida krusei were the pathogenic fungal test strains used to determine the MIC value of caerulomycin A. The MIC values reported ranged between 0.39 and 1.56 µg/mL [23,24].
The secondary metabolite, pedein A (6 in Scheme 1), was isolated from the cell mass of the myxobacterium Chondromyces pediculatus. Pedein A inhibited the growth of a broad spectrum of yeasts and fungi, whereas Gram-positive and Gram-negative bacteria such as Bacillus subtilis, Brevibacterium ammoniagenes, Corynebacterium fascians, Micrococcus luteus, Staphylococcus aureus, Escherichia coli, Enterobacter aerogenes, Pseudomonas aeruginosa, and Salmonella typhimurium were not sensitive to the antibiotic. MIC value for Rhodotorula glutinis was reported to be 0.6 µg/mL, and an MIC value of 1.6 µg/mL was reported for both Saccharomyces cerevisiae and Candida albicans. Furthermore, pedein A showed inhibitory activity against the growth of some filamentous fungi with a zone diameter range of 22-35 mm for Botrytis cinerea, Gibberella fujikuroi, Pythium debaryanum, Rhizopus arrhizus, Trichoderma koningii, and Ustilago maydis [20,21].
Other important isolated antifungal compounds, their marine sources, and their activities are listed in Table 1.

Antifungal Compounds Isolated from Marine Fungi
From the ocean's surface to its deepest parts, fungi have been discovered to exist in almost every aquatic habitat studied [25]. As a result of marine fungi's superior biological characteristics to terrestrial fungi and their ability to adapt to extreme pH, temperature, and salinity, a wider range of biotechnological applications of marine fungi are possible [26].

Antifungal Compounds Isolated from Marine Algae
Caulerprenylol B (25 in Scheme 1), which was obtained from Chinese alga Caulerpa racemosa, has excellent antifungal activity against T. rubrum fungus, which causes two of the most common fungal infections, known as 'athlete's foot' and 'jock itch', with an MIC 80   The growth of Cryptococcus neoformans, Richophyton rubrum, C. albicans, C. tropicalis, A. fumigatus, and C. krusei could be inhibited with MIC 80 values ranging from 0.7 to 2.81 µM by marmoratoside A, impatient side A, and bivittoside D (32-34 in Scheme 1) isolated from Bohadschia marmorata Jaeger [49,50].

Antifungal Compounds Isolated from Sea Sponges
Sponges are elementary multi-cellular animals with dense skeleton muscles. They have a vast repertoire of antifungal compounds, which are useful in cases of resistance to amphotericin B and fluconazole [51].
The growth of C. albicans was inhibited by the isolated epiplakinic acid F (35, in Scheme 1) and agelasidine F and C (36,37 in Scheme 1), which have MIC values of 3.1, 4, and 0.5 µg/mL, respectively. Epiplakinic acid F was extracted from the Seychelles sponge genus Plakinastrella. Agelasidine F and C were obtained from Agelas citrina (Caribbean sponge) [51][52][53]. Table 2 lists other isolated compounds from sea sponges that exhibit antifungal activity against C. albicans. The highly oxygenated alkaloid massadine (38 in Scheme 1), which was isolated from the marine sponge Stylissa aff. massa, inhibited Geranylgeranyltransferase-I from C. albicans with an IC50 value of 3.9 µM. Moreover, massadine inhibited the growth of Cryptococcus neoformans with an MIC value of 32 µM, but it did not inhibit the growth of C. albicans at a concentration of 64 µM [53].
A reasonably new nematicide (a substance active against nematode worms), onnamide F (56 in Scheme 1), which was isolated from Trachycladus laevispirulifer, is helpful in Saccharomyces cerevisiae or baker's yeast infections. It has an LD 99 (dosage required to kill 99% of the fungi population) of 1.4 µg/mL [68].
Fluconazole resistance has been increasing recently, specifically in immunocompromised individuals such as HIV patients prescribed fluconazole prophylactically. Because of that, other antifungal compounds have been screened for efficacy in resistant strains. Geodisterol-3-O-sulfite and 29-demethylgeodisterol-3-O-sulfite, active constituents of Topsentia sp. extracts, have been used in fluconazole-resistant strains. Many Saccharomyces cerevisiae strains can overexpress the MDR1 efflux pump (a pump responsible for pumping out toxic substances such as fluconazole). Hence, these two compounds have been used in reverse [69].

Ribosomal Peptides-Antimicrobial Peptides
Antimicrobial peptides (AMPs) are large, amphipathic molecules synthesized by ribosomes using 12-45 amino acids, which typically have a tertiary structure (conformation). Due to their broad-spectrum antibacterial properties, they are suited for targeting prokaryotic cell membranes. AMPs are different from the adaptable lymphocyte-based immunity that characterizes higher vertebrates. AMPs that are produced by bacteria are named bacteriocins. In multicellular organisms, AMPs are found on the external surfaces (skin) or within the neutrophils. Marine invertebrates have their AMPs in cells that are similar to neutrophiles called hemocytes. Due to the presence of a good amount of lysine, arginine, and histidine and a low amount of acidic and neutral amino acids, AMPs are highly cationic at physiological pH. In addition to possessing phospholipids with no net charge, this cationic nature gives AMPs selectivity and selective toxicity towards bacterium cells, and their amphipathic nature may help explain their antibacterial effect [5,70,71].
Halocidin is derived from the tunicate Halocynthia aurantium's hemocytes [76]. The translated peptide consists of a halosidine segment, a single glycine residue, an N-terminal signal peptide, a C-terminal anion extension, and a single glycine residue (58 in Scheme 1) [77]. On the other hand, the modified active peptide comprises two peptides, one with 15 amino acids and the other with 18, joined by a disulfide bond. Halocidin congeners, called Khal, appeared to have potent antibacterial action against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and segregates of polyresistant Pseudomonas aeruginosa with MICs within the range of 2-4 µg/mL. One of two derivatives showed promising results in an animal model of Listeria monocytogenes infection [78].
Hedistin (59 in Scheme 1) is an amphipathic antibacterial polypeptide obtained from Nereis diversicolor coelomocytes, a marine annelid worm [79]. This peptide had a high MIC of 1-2 µg/mL against Micrococcus luteus and Micrococcus nishinomiyaensis, indicating that it was effective against Gram-positive bacteria. The synthesized peptide was effective against S. aureus, with MIC values ranging from 8 to 15 µg/mL, as well as other Staphylococcus species [80].
Clavanin A (60 in Scheme 1) peptide that isolated from the hemocytes of the Styela clava. [81,82] Clavanin A is rich in phenylalanine amino acids, which can replace it with other hydrophobicity amino acids without losing antibacterial activity [83]. Clavanin A showed potent antibacterial activity against Gram-positive as well as Gram-negative bacteria [84]. Clavanin's MIC against S. aureus, including methicillin-resistant S. aureus strains, equals 1.4 to 3.8 µg/mL. Three strains of Enterococcus faecium had MIC values ranging from 0.1 to 1.1µg/mL. Strains of E. coli with an MIC value ranging from 0.4 to 2.3 µg/mL and three strains of P. aeruginosa with an MIC value ranging from 0.4 to 0.8 µg/mL were likewise susceptible to clavanin A [85,86].

Nonribosomal Peptides
Large multifunctional protein complexes called nonribosomal peptide synthetases (NRPSs) produce nonribosomal peptides [87]. The DNA does not encode many nonproteinogenic amino acids in these peptides. The most common nonribosomal peptides with antibacterial activity include bogorol A (61 in Scheme 1), which was isolated from Bacillus laterosporus bacterium. It was confirmed that bogorol A showed activity in oppo-sition to Methicillin-resistant S. aureus with an MIC of 2.5 µg/mL as well as vancomycinresistant Enterococcus with an MIC of 9 µg/mL [88]. The cationicity of bogorol A has a significant role in targeting the bacterial membrane.
Bleich et al. [92] described YM-266183 (64 in Scheme 1) as an antibacterial peptide. It was produced by Bacillus cereus isolated from a marine sponge Halichondria japonica. The peptide is highly active against Gram-positive bacteria, including S. aureus and Enterococci, with MIC values of 0.68 µg/mL and 0.025 µg/mL, respectively [92,93].

Polyketides
Bisanthraquinone metabolites BE-43472B and BE-43472A (65,66 in Scheme 1) isolated from a marine streptomycete showed biological activities against clinically derived isolates of E. faecium as well as S. aureus. The most potent activity displayed MIC values of 0.23 and 0.90 µg/mL against a panel (n = 25 each) of clinical MRSA and VRE, respectively [10,94].
Pestalone (68 in Scheme 1), which is produced by a cultured marine fungus isolated from the brown alga Rosenvingea sp., showed potent antibiotic activity against methicillinresistant S. aureus as well as vancomycin-resistant bacteria with MIC values of 37 µg/mL and 78 µg/mL, respectively [96,97]. Table 3 lists some other isolated polyketide compounds.
The bromopyrrole alkaloid nagelamides G (75 in Scheme 1), which was isolated from the Okinawan marine sponge Agelas sp., exhibited antibacterial activity against Gram-positive bacteria M. luteus and B. subtilis with MIC values of 2.08 and 16.7 µg/mL, respectively [106].
With MIC values of 0.625 and 1.25 µg/mL, ambiguine H isonitrile (76 in Scheme 1) obtained from Fischerella sp. showed activity against Scaphirhynchus albus and B. subtilis, respectively. Furthermore, ambiguine I isonitrile (77 in Scheme 1) exhibited antibacterial inhibitory activities against the same bacterial strains with MIC values of 0.078 and 0.312 µg/mL, respectively [107]. Furthermore, cribrostain 6 (78 in Scheme 1), which was isolated from the blue marine sponge Cribrochalina sp., showed an antibacterial activity against the same bacterial strain with MIC values of 16 and 2 µg/mL, respectively [108].
Staphylococcus aureus (methicillin-resistant S. aureus) and Mycobacterium intracellulare were both inhibited with MIC values of 5 and 10 µg/mL, respectively, by batzelladine M (79 in Scheme 1). Additionally, antibacterial inhibitory activities against P. aeruginosa were also shown by batzelladine L (80 in Scheme 1) with MIC values ranging from 0.31 to 20 µg/mL. Batzelladine L and batzelladine M are two polycyclic guanidine alkaloids extracted from the Jamaican sponge Monanchora unguifera [109]. Antibacterial inhibitory activities were also ascertained for lynamicins A-D (81 in Scheme 1), which were isolated from a marine actinomycete, NPS12745, with MIC values ranging between 1.8 and 9.5 µg/mL [110].
Marinopyrroles A and B (82 in Scheme 1), which were both isolated from marine Streptomyces strain bacterium, exhibited strong antibiotic activities against MRSA, with an MIC value range of 0.31-0.61 µg/mL [111].

Terpenes
Terpenes are a diverse class of natural products composed of repeating isoprene units. They include hemiterpenes (C5), di-unit monoterpenes (C10), tri-unit sesquiterpenes (C15), tetra-unit diterpenes (C20), penta-unit sesterterpenes (C25), and so on. They are created when mono-isoprene is broken down one unit at a time. Skeletal rearrangements, which frequently take place, alter the normal head-to-tail orientation of the isoprene units and add variety to the terpenoid structures [112].
The isolated xeniolide I diterpenes (83 in Scheme 1) from soft coral Xenia novaebrittanniae shows activity against B. subtilis and E. coli with MIC values of 1.00 and 1.25 µg/mL, respectively [113,114].

Conclusions
To sum up everything that has been stated so far, this review shed light on 96 compounds isolated from a variety of marine organisms and showed promising activities against bacteria and fungi. These compounds show great potential for the development of novel antibiotic drugs that can help overcome the problem of antibiotic resistance and have the potential to decrease treatment failures in humans, as many of these compounds showed powerful activities against antibiotic-resistant strains of bacteria and fungi such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant bacteria, and many others.
Currently, a significant portion of the novel antifungal and antibacterial drugs in clinical trials was derived from marine species, particularly bacteria as well as sponges. Given the vast number of undiscovered compounds in the oceans, all the new compounds identified might only be the tip of the iceberg, which is quite significant.