Marine Macrolides with Antibacterial and/or Antifungal Activity

Currently, the increasing resistance of microorganisms to antibiotics is a serious problem. Marine organisms are the source of thousands of substances, which also have antibacterial and antifungal effects. Among them, marine macrolides are significant. In this review, the antibacterial and/or antifungal activities of 34 groups of marine macrolides are presented. Exemplary groups are chalcomycins, curvulides, halichondramides, lobophorins, macrolactins, modiolides, scytophycins, spongistatins, or zearalanones. In the paper, 74 antibiotics or their analog sets, among which 29 with antifungal activity, 25 that are antibacterial, and 20 that are both antifungal and antibacterial are summarized. Also, 36 macrolides or their sets are produced by bacteria, 18 by fungi, ten by sponges, seven by algae, two by porifera, and one by nudibranch. Moreover, the chemical structures of representatives from each of the 34 groups of these antibiotics are presented. To summarize, marine organisms are rich in natural macrolides. Some of these may be used in the future in the treatment of bacterial and fungal infections. Marine macrolides can also be potential drugs applicable against pathogens resistant to currently known antibiotics.


Introduction
The marine world is rich in species and very diverse. Thus, marine organisms are a source of many substances with biological activity, including cytotoxic and antimicrobial. According to Burja et al., it was determined that in the marine world, there are over 13,000 unique compounds [1]. Important marine groups containing biologically active substances, including macrolides, are, among others, sponges [2] and cyanobacteria [3]. Swian et al. only described 121 compounds with antimicrobial activity among cyanobacteria, including the following chemical classes: alkaloids, aromatic compounds, pigments, fatty acids, phenols, macrolides, peptides, polyketides, porphinoids, and terpenoids [4]. Liu et al. described 118 marine macrolides, most with cytotoxic activity [5].
Macrolides are a group of polyketides. Currently, few of these substances are used in medicine. Among the antibacterial macrolides, the most important are erythromycin, azithromycin, roxithromycin, clarithromycin, josamycin, and spiramycin; among ketolides, telithromycin [6]. On the other hand, among antifungal polyene macrolides, amphotericin B, nystatin, and natamycin are most often used [7]. In general, antibacterial macrolides are active against Staphylococcus sp., Streptococcus sp., Neisseria gonorrhoea, Haemophilus influenzae, Bordetella pertussis, and Neisseria meningitis. Additionally, they are used in infections caused by intracellular pathogens, Mycoplasma sp. and Chlamydia sp. [8,9]. Clarithromycin is one of the antibiotics used in Helicobacter pylori infections [10]. The action of antibacterial macrolides is bacteriostatic. They reversibly bind to 23S ribosomal RNA of the 50s subunit of the bacterial ribosome inhibiting RNA-dependent protein synthesis [11]. The antifungal macrolides bind to ergosterol and lead to pore formation, leakage of monovalent ions (K + , Na + , H + and Cl − ), and finally to fungal cell death [12].
against Micrococcus luteus (MIC = 16.7 mg/mL) and antifungal activity against Neurospora crassa (MIC = 33.3 mg/mL) [27]. Modiolide A is also the secondary metabolite of the marine-derived fungus Curvularia sp. Modiolide A and at least four substances resembling 10-membered lactones but featuring modified oxidation patterns around their macrocycles were shown to occur in this species [20]. In other studies, it was demonstrated that modiolide A obtained from Curvularia sp. strain M12, acts against the fungus-like eukaryotic microorganism Phytophthora capsici, leading to the disorder of zoospore motility at high concentrations (IC 50 : 50-100 µg/mL) [21]. Trisuvan et al. showed a lack of modiolide A activity against strains Staphylococcus aureus ATCC 25923, methicillin-resistant S. aureus, and Microsporum gypseum SH-MU-4 at the initial concentration of 200 µg/mL [26].

Xestodecalactones
Xestodecalactones A-C, were obtained from an isolate of the fungus Penicillium cf. montanense from the marine sponge Xestospongia exigua collected from the Bali Sea, Indonesia. Among these metabolites, xestodecalactone B was found to have anti-fungal activity against the yeast Candida albicans at concentrations of 20 µM and higher. Simultaneously, xestodecalactones A-C ( Figure 1d) were inactive toward the bacteria Bacillus subtilis, Staphylococcus aureus, and Escherichia coli [32,33]. Xestodecalactones D-F obtained from Corynespora cassiicola, isolated from the Chinese mangrove plant Laguncularia racemosa, neither showed antibacterial nor antifungal activity [34]. Micrococcus luteus (MIC = 16.7 mg/mL) and antifungal activity against Neurospora crassa (MIC = 33.3 mg/mL) [27]. Modiolide A is also the secondary metabolite of the marine-derived fungus Curvularia sp. Modiolide A and at least four substances resembling 10-membered lactones but featuring modified oxidation patterns around their macrocycles were shown to occur in this species [20]. In other studies, it was demonstrated that modiolide A obtained from Curvularia sp. strain M12, acts against the fungus-like eukaryotic microorganism Phytophthora capsici, leading to the disorder of zoospore motility at high concentrations (IC50: 50-100 μg/mL) [21]. Trisuvan et al. showed a lack of modiolide A activity against strains Staphylococcus aureus ATCC 25923, methicillin-resistant S. aureus, and Microsporum gypseum SH-MU-4 at the initial concentration of 200 μg/mL [26].

Xestodecalactones
Xestodecalactones A-C, were obtained from an isolate of the fungus Penicillium cf. montanense from the marine sponge Xestospongia exigua collected from the Bali Sea, Indonesia. Among these metabolites, xestodecalactone B was found to have anti-fungal activity against the yeast Candida albicans at concentrations of 20 μM and higher. Simultaneously, xestodecalactones A-C ( Figure 1d) were inactive toward the bacteria Bacillus subtilis, Staphylococcus aureus, and Escherichia coli [32,33]. Xestodecalactones D-F obtained from Corynespora cassiicola, isolated from the Chinese mangrove plant Laguncularia racemosa, neither showed antibacterial nor antifungal activity [34].

Lobophorins
Lobophorins A ( Figure 3a) and B were isolated from a marine Actinomycete strain #CNB-837 isolated from the surface of the Caribbean brown alga Lobophora variegata [41,42]. Spirotetronate antibiotics; lobophorins E and F, were isolated from Streptomyces sp. SCSIO 01127 obtained from sediment in the South China Sea [40]. Lobophorins H and I were obtained from Streptomyces sp. strain 12A35, which was isolated from the deep-sea sediment of the South China Sea [43].

Leucascandrolides
Leucascandrolide A (Figure 5c) [56] was isolated from the calcareous sponge Leucascandra caveolata, collected along the east coast of the Coral Sea, New Caledonia. This compound strongly inhibited fungi Fusarium oxysporum, Helminthosporium sativum, Phytophthora hevea, Botrytis cinerea, Pyricularia oryzae, and yeast Candida albicans [57]. Figure 5b) is an 18-membered macrolide, which was isolated from the sponge Mycale adhaerens in Japan [58]. This macrolide strongly binds to the 60S large ribosomal subunit, causing inhibition of polypeptide elongation in fungus Saccharomyces cerevisiae, however it does not inhibit the polypeptide synthesis in bacterium Escherichia coli [59].

Leucascandrolides
Leucascandrolide A (Figure 5c) [56] was isolated from the calcareous sponge Leucascandra caveolata, collected along the east coast of the Coral Sea, New Caledonia. This compound strongly inhibited fungi Fusarium oxysporum, Helminthosporium sativum, Phytophthora hevea, Botrytis cinerea, Pyricularia oryzae, and yeast Candida albicans [57]. (Figure 5b) is an 18-membered macrolide, which was isolated from the sponge Mycale adhaerens in Japan [58]. This macrolide strongly binds to the 60S large ribosomal subunit, causing inhibition of polypeptide elongation in fungus Saccharomyces cerevisiae, however it does not inhibit the polypeptide synthesis in bacterium Escherichia coli [59].

Misakinolides
According to Sakai et al. misakinolide A (Figure 6b) is a 20-membered macrolide [62], however this macrolide occurs as 40-membered dimer [63]. Misakinolide A was isolated from the sponge Theonella sp., collected at Maeda-misaki, Okinawa, Japan. This compound possesses antifungal activity against Candida albicans (MIC 5 μg/mL) [62].  ) is an 18-membered macrolide, which was isolated from the sponge Mycale adhaerens in Japan [58]. This macrolide strongly binds to the 60S large ribosomal subunit, causing inhibition of polypeptide elongation in fungus Saccharomyces cerevisiae, however it does not inhibit the polypeptide synthesis in bacterium Escherichia coli [59].

Kabiramides
Kabiramide C (Figure 7a) was isolated from the eggmasses of an unidentified nudibranch collected at Kabira Bay on Ishigaki-jima Island of the Ryukyus Islands, Japan. This 22-membered macrolide showed marked antifungal activity against Candida albicans ATCC 10234, Aspergillus niger ATCC 9642, Penicillium citrium ATCC 9849 and Trichophyton interdigitale [64]. Kabiramides G, J and K were isolated from the sponge Pachastrissa nux collected in the Gulf of Thailand. These macrolides, together with kabiramides B-D, showed anti-parasite activity against Plasmodium falciparum K1 [65].

Halichondramides
An oxazole-containing macrolide, halichondramide (Figure 8b), is a 25-membered antibiotic [72]. It was obtained from the sponge Halichondria sp. from Kwajalein Island, Marshall Islands, and showed significant activity against Candida albicans (MIC 0.2 pg/mL) and Trichophyton mentagrophytes (MIC 12.5 pg/mL). Halichondramide did not inhibit bacteria [73]. Further studies revealed that the sponge of the genus Halichondria sp. also contains two other macrolides (dihydrohalichondramide and isohalichondramide) having significant activity against C. albicans. In this same paper, the authors showed that anti-C. albicans activity had the nudibranch Hexabranchus sanguineus, from which dihydrohalichondramide and tetrahydrohalichondramide were isolated [74]. From the marine sponge Chondrosia corticata collected from Guam, more oxazole-containing macrolides were isolated: neohalichondramide, (19Z)-halichondramide, and secohalichondramide. These compounds exhibited antifungal activity toward the Candida albicans and Aspergillus niger [75]. Chung

Macrolactins
Macrolactins are a big group of 22-to 25-membered lactone macrolides. Some of these were isolated from a culture of Bacillus sp. PP19-H3 obtained from the macroalga Schizymenia dubyi collected on the Omaezaki coast of Shizuoka prefecture in Japan. Macrolactins A (Figure 8c), F, G, I, J, K, and L are 24-membered macrolides, macrolactin H is 22-membered, and macrolactin is M a 25-membered lactone. Macrolactins A, G, H, I, J, L, and M were effective against Staphylococcus aureus (MICs 5-10 ppm), and Bacillus subtilis (MICs 30-60 ppm). The macrolactins F and K had low activity against the above bacteria (MICs 80 and >100). None of the studied macrolides inhibited Escherichia coli or Salinivibrio costicola [77,78]. In other studies, macrolactin A did not have any antimicrobial activity [79,80].  [79,80].
Macrolactin N was obtained from Bacillus subtilis AT29 and had antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. It inhibited the growth of E. coli with a MIC value of 100 µg/mL, while for S. aureus and B. subtilis, the MIC 50 is 100 µg/mL. Macrolactin N inhibited S. aureus peptide deformylase with an IC 50 value of 7.5 µM [81].
From the marine Bacillus sp. derived from the sea sediment of East China Sea, macrolactin S, a 24-membered ring lactone, was obtained. Macrolactin S, together with macrolactins A and B had antibacterial activity against Escherichia coli, and Staphylococcus aureus [82].
Macrolactins T and U, along with macrolactins A, B, D, O, and S, were isolated from the bacterium Bacillus marinus, which was separated from Suaeda salsa collected in the coastline of the Bohai Sea of China. In the study, authors reported the inhibitory activity of macrolactins B (MIC 4.5-20.1 µg/mL) and D (MIC > 100 µg/mL) against fungi Pyricularia oryzae and Alternaria solani, and bacterium Staphylococcus aureus [83].
From marine bacterium B. amyloliquefaciens SCSIO 00856 isolated from the South China Sea gorgonian Junceella juncea, macrolactin V and S. Macrolactin V were obtained and had strong antibacterial activities against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus with a MIC value of 0.1 µg/mL. Macrolactin S showed potent activity against E. coli and S. aureus (MICs 0.1-0.3 µg/mL), and weak against B. subtilis (MIC 100 µg/mL) [84].
Macrolactin W was isolated from a marine Bacillus sp. 09ID194 collected from Ieodo, a southern reef of South Korea. This macrolide showed antibacterial activities towards Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa with a MIC of 64 µg/mL [85].
One of the marine Bacillus sp. produces three 24-membered macrolactins, which contain an oxetane, an epoxide, and a tetrahydropyran ring, respectively. All three macrolactins showed antimicrobial activity against Bacillus subtilis and Escherichia coli (MIC 0.16 µM). The macrolactin with an epoxide ring also had excellent activity against Saccharomyces cerevisiae (MIC 0.02-0.16 µM) [86].
From Bacillus subtilis MTCC 10403, isolated from the brown seaweed Anthophycus longifolius collected from the Gulf of Mannar of India, new antimicrobial aryl-crowned polyketide macrolactin was obtained. This substance had bactericidal properties against Escherichia coli, Aeromonas hydrophilla, Pseudomonas aeruginosa, and Vibrio sp. at a low concentration with MIC < 13 µg/mL, and against Klebsiella pneumoniae with MIC~25 µg/mL. The mode of antimicrobial action of this new acryl-crowned macrolactin was found to be iron chelating similar to siderophores [87].

Maduralide
Maduralide (Figure 8d) is 24-membered ring macrolide. It was isolated from an unidentified marine bacterium of the order Actinomycetales in the shallow waters of Bodega Bay, USA. Maduralide shows weak antibiotic activity against Bacillus subtilis [88].
Macrolactin N was obtained from Bacillus subtilis AT29 and had antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. It inhibited the growth of E. coli with a MIC value of 100 μg/mL, while for S. aureus and B. subtilis, the MIC50 is 100 μg/mL. Macrolactin N inhibited S. aureus peptide deformylase with an IC50 value of 7.5 μM [81].
From the marine Bacillus sp. derived from the sea sediment of East China Sea, macrolactin S, a 24-membered ring lactone, was obtained. Macrolactin S, together with macrolactins A and B had antibacterial activity against Escherichia coli, and Staphylococcus aureus [82].
Macrolactins T and U, along with macrolactins A, B, D, O, and S, were isolated from the bacterium Bacillus marinus, which was separated from Suaeda salsa collected in the coastline of the Bohai Sea of China. In the study, authors reported the inhibitory activity of macrolactins B (MIC 4.5-20.1 μg/mL) and D (MIC > 100 μg/mL) against fungi Pyricularia oryzae and Alternaria solani, and bacterium Staphylococcus aureus [83].
From marine bacterium B. amyloliquefaciens SCSIO 00856 isolated from the South China Sea gorgonian Junceella juncea, macrolactin V and S. Macrolactin V were obtained and had strong antibacterial activities against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus with a MIC value of 0.1 μg/mL. Macrolactin S showed potent activity against E. coli and S. aureus (MICs 0.1-0.3 μg/mL), and weak against B. subtilis (MIC 100 μg/mL) [84].
Macrolactin W was isolated from a marine Bacillus sp. 09ID194 collected from Ieodo, a southern reef of South Korea. This macrolide showed antibacterial activities towards Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa with a MIC of 64 μg/mL [85].
One of the marine Bacillus sp. produces three 24-membered macrolactins, which contain an oxetane, an epoxide, and a tetrahydropyran ring, respectively. All three macrolactins showed antimicrobial activity against Bacillus subtilis and Escherichia coli (MIC 0.16 μM). The macrolactin with an epoxide ring also had excellent activity against Saccharomyces cerevisiae (MIC 0.02-0.16 μM) [86].
From Bacillus subtilis MTCC 10403, isolated from the brown seaweed Anthophycus longifolius collected from the Gulf of Mannar of India, new antimicrobial aryl-crowned polyketide macrolactin was obtained. This substance had bactericidal properties against Escherichia coli, Aeromonas hydrophilla, Pseudomonas aeruginosa, and Vibrio sp. at a low concentration with MIC < 13 μg/mL, and against Klebsiella pneumoniae with MIC ~25 μg/mL. The mode of antimicrobial action of this new acryl-crowned macrolactin was found to be iron chelating similar to siderophores [87].

Maduralide
Maduralide (Figure 8d) is 24-membered ring macrolide. It was isolated from an unidentified marine bacterium of the order Actinomycetales in the shallow waters of Bodega Bay, USA. Maduralide shows weak antibiotic activity against Bacillus subtilis [88].

Phorboxazoles
Phorboxazoles A (Figure 9b) and B were isolated from the Indian Ocean marine sponge Phorbas sp. Both antibiotics had antifungal activity against Candida albicans and Saccharomyces carlsbergensis. None of these compounds showed any activity against Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus [90].

Phorboxazoles
Phorboxazoles A (Figure 9b) and B were isolated from the Indian Ocean marine sponge Phorbas sp. Both antibiotics had antifungal activity against Candida albicans and Saccharomyces carlsbergensis. None of these compounds showed any activity against Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus [90].

Phorboxazoles
Phorboxazoles A (Figure 9b) and B were isolated from the Indian Ocean marine sponge Phorbas sp. Both antibiotics had antifungal activity against Candida albicans and Saccharomyces carlsbergensis. None of these compounds showed any activity against Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus [90].

Bahamaolides
From the marine actinomycete Streptomyces sp. CNQ343 derived from sediment collected at North Cat Cay in the Bahamas, bahamaolides A and B. Bahamaolide A (Figure 11b) displaying significant inhibitory activity against Candida albicans ATCC 10231 with a MIC value of 12.5 µg/mL acting on enzyme isocitrate lyase were isolated. It also possessed antifungal activity against various pathogenic fungi: Aspergillus fumigatus HIC 6094, Trichophyton rubrum IFO 9185, T. mentagrophytes IFO4 0996. Bahamaolide B did not inhibit any tested strain [96].

Macrolides 40-Membered
Amantelides Amantelides A (Figure 11d) and B were isolated from gray cyanobacterium belonging to the family Oscillatoriales, collected near Puntan dos Amantes, Tumon Bay, Guam. The antifungal activity of amantelide A was observed against the marine fungi Dendryphiella salina, Lindra thalassiae, and Fusarium sp. at a concentration of 62.5 µg/mL. Moreover, macrolide had weak antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa with a MIC of 32 µM. Amantelide B inhibited the growth of Dendryphiella salina at a concentration of 6.25 µg/mL [99]. antifungal activity against Candida albicans ATCC10231 [97]. PM100117 also showed antibiotic activity against Saccharomyces cerevisiae W303.1A but was not active towards Micrococcus luteus [98].

Macrolides 40-Membered
Amantelides Amantelides A (Figure 11d) and B were isolated from gray cyanobacterium belonging to the family Oscillatoriales, collected near Puntan dos Amantes, Tumon Bay, Guam. The antifungal activity of amantelide A was observed against the marine fungi Dendryphiella salina, Lindra thalassiae, and Fusarium sp. at a concentration of 62.5 μg/mL. Moreover, macrolide had weak antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa with a MIC of 32 μM. Amantelide B inhibited the growth of Dendryphiella salina at a concentration of 6.25 μg/mL [99].

Spongistatins
The spongistatins are macrocyclic lactone polyethers isolated from marine porifera. Spongistatin 1 (Figure 12) was discovered in an Indian Ocean Spongia species [100] and Hyrtios erecta together with spongistatins 2 and 3 [101]. Spongistatins 4-7 were obtained from the southeast African Spirastrella spinispirulifera [102,103]. All of these antibiotics inhibited the growth of Candida albicans and Cryptococcus neoformans in disk diffusion assays. Furthermore, Spongistatin 1 acted against Issatchenkia orientalis, Rhodotorula mucilaginosa, Aspergillus fumigatus, and Rhizopus oligosporus with MICs of 0.195-12.5 μg/mL [104]. In Table 1 has been presented the general characteristic of marine macrolides described in this review. In Table 1 has been presented the general characteristic of marine macrolides described in this review.

Conclusions
Marine organisms produce 34 groups of macrolides with antibacterial and/or antifungal activities. Among seventy-six antibiotics or their analog sets summarized in the Table, 36 are produced by bacteria, 18 by fungi, ten by sponges, seven by algae, two by porifera and one by nudibranch. At the same time, 29 macrolides or their groups have antifungal activity, 25 have antibacterial, and 20 have both antifungal and antibacterial. Summarizing, marine organisms are abundant in natural macrolides, which may be used in the future for the treatment of bacterial and fungal infections. Marine macrolides can also be potential drugs applicable against pathogens resistant to currently known antibiotics, which is also presented in other papers [105][106][107].