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Antibiotic resistance and residues in aquaculture are a growing concern worldwide and consequently identifying favorable antibacterial compounds against aquatic pathogenic bacteria are gained more attention. Active compounds derived from marine microorganisms have shown great promise in this area. The antibacterial compounds used in aquaculture are the same used in medicine and veterinary fields. Even though antibiotics are convenient and effective as drugs for the prophylaxis and treatment of bacterial diseases in aquaculture animals, the long-term application or abuse of antibiotics has made antibiotics less and less effective, and mutant pathogens often cause more severe disease. In addition, antibiotic residues in aquatic products directly threaten human health. Therefore, it is urgent to develop new antibacterial agents for aquatic products.
- antibacterial molecules
- aquatic bacterial pathogens
- marine microorganisms
1. Marine Bacterial Compounds against Aquatic Pathogenic Bacteria
Marine microbes, especially bacteria and fungi, are excellent producers of natural products with diverse structures and pharmacological activities, and marine microbes serve as valuable resources in the ongoing search for antibacterial compounds against aquatic pathogens [11,12][1][2].
A cyclic lipopeptide N3 produced by B. amyloliquefaciens M1 was identified as surfactin (1, Figure 1). The minimal inhibitory concentration (MIC) of the purified lipopeptide N3 against V. anguillarum was 1.5 μg/mL[13][3]. 3-(octahydro-9-isopropyl-2H-benzo[h]chromen-4-yl)-2-methylpropyl benzoate (2) and methyl 8-(2-(benzoyloxy)-ethyl)-hexahydro-4-((E)-pent-2-enyl)-2H-chromene-6-carboxylate (3) are two polyketides with activity against Vibrio vulnificus and were isolated from the ethyl acetate extract of B. amyloliquefaciens associated with edible red seaweed, Laurenciae papillosa. The compounds 2 and 3 demonstrated significant antibacterial activity against V. vulnificus (inhibitory zone diameter of 18.00 ± 1.00 mm and 16.67 ± 0.58 mm, 25 mcg on disk) [14][4]. Three polyketides from Bacillus amyloliquefaciens associated with seaweed Padina gymnospora were characterized as 11-(15-butyl-13-ethyl-tetrahydro-12-oxo-2H-pyran-13-yl) propyl-2-methylbenzoate (4), 9-(tetrahydro-12-isopropyl-11-oxofuran-10-yl)-ethyl-4-ethoxy-2-hydroxybenzoate (5), and 12-(aminomethyl)-11-hydroxyhexanyl-10-phenylpropanoate (6). Compounds 4–6 displayed significant antibacterial activities against V. vulnificus MTCC 1145, A. hydrophila MTCC 646, and V. vulnificus MTCC 1145 with inhibitory zone diameters of 16.33 ± 0.58 mm, 14.67 ± 1.15 mm, and 17.33 ± 1.00 mm (10 mcg on disk), respectively [15][5].
Figure 1. Structures of marine bacterial compounds against aquatic pathogenic bacteria, surfactin (1), 3-(octahydro-9-isopropyl-2H-benzo[h]chromen-4-yl)-2-methylpropyl benzoate (2), methyl 8-(2-(benzoyloxy)-ethyl)-hexahydro-4-((E)-pent-2-enyl)-2H-chromene-6-carboxylate (3), 11-(15-butyl-13-ethyl-tetrahydro-12-oxo-2H-pyran-13-yl) propyl-2-methylbenzoate (4), 9-(tetrahydro-12-isopropyl-11-oxofuran-10-yl)-ethyl-4-ethoxy-2-hydroxybenzoate (5), 12-(aminomethyl)-11-hydroxyhexanyl-10-phenylpropanoate (6), 7-O-6′-(2”-acetylphenyl)-5′-hydroxyhexanoate-macrolactin (7), 7,7-bis(3-indolyl)-p-cresol (8), cyclo-(S-Pro-R-Val) (9), 2-(7-(2-Ethylbutyl)-2,3,4,4a,6,7-hexahydro-2-oxopyrano-[3,2b]-pyran-3-yl)-ethyl benzoate (10), 2-((4Z)-2-ethyl-octahydro-6-oxo-3-((E)-pent-3-enylidene)-pyrano-[3,2b]-pyran-7-yl)-ethyl benzoate (11), tropodithietic acid (12), phenazine-1-carboxylic acid (13), tirandamycin A (14), and tirandamycin B (15).
Antibacterial aryl-crowned polyketide, 7-O-6′-(2”-acetylphenyl)-5′-hydroxyhexanoate-macrolactin (7) was isolated from Bacillus subtilis MTCC 10,403 associated with brown seaweed Anthophycus longifolius. The MIC assay showed that compound 7 displayed potential antibacterial activities against significant Gram-negative pathogens with MIC of 3.12 μg/mL against V. vulnificus, 6.25 μg/mL against A. hydrophilla, 12.5 μg/mL against V. parahaemolyticus and P. aeruginosa [16]aeruginosa [6]. Two compounds including 7,7-bis(3-indolyl)-p-cresol (8) and cyclo-(S-Pro-R-Val) (9) were isolated from the strain of Bacillus megaterium LC derived from the marine sponge Haliclona oculata. Compound 8 displayed antibacterial activity at MIC values of 0.05 μg/mL and 0.005 μg/mL against V. vulnificus and M. luteus. Compound 9 showed antimicrobial activity at MIC value of 0.05 μg/mL against V. parahaemolyticus [17]parahaemolyticus [7].
O-heterocyclic derivatives with antibacterial properties were isolated from B. subtilis MTCC 10,407 associated with brown seaweed Sargassum myriocystum, and identified as 2-(7-(2-Ethylbutyl)-2,3,4,4a,6,7-hexahydro-2-oxopyrano-[3,2b]-pyran-3-yl)-ethyl benzoate (10) and 2-((4Z)-2-ethyl-octahydro-6-oxo-3-((E)-pent-3-enylidene)-pyrano-[3,2b]-pyran-7-yl)-ethyl benzoate (11). Compounds 10 and 11 showed significant antibacterial activity (inhibitory zone diameters of 17.66 ± 0.58 mm and 15.3 ± 1.0 mm, 10 μg on disk) against A. hydrophilla [18]hydrophilla [8].
An antimicrobial compound produced by Pseudovibrio sp. P12, a common and abundant coral-associated bacterium, was identified as tropodithietic acid (12), with the MIC value of 0.5 μg/mL against Vibrio coralliilyticus and Vibrio owensii [19][9]. A phenazine derivative against V. anguillarum was isolated from Pseudomonas aeruginosa strain PA31x and demonstrated to be phenazine-1-carboxylic acid (13) with the MIC value of 50 μg/mL for V. anguillarum [20]anguillarum [10]. Tirandamycins A (14) and B (15) were isolated from the crude extract of Streptomyces tirandamycinicus sp. nov., a novel marine sponge-derived actinobacterium. Compounds 14 and 15 showed potent antibacterial activity against Streptococcus agalactiae with MIC values of 2.52 and 2.55 μg/mL, respectively [21][11].
2. Marine Aspergillus
Marine fungi have become the main source of natural products of marine microorganisms due to their complex genetic background, structural diversity and high yields of metabolites. New natural products derived from marine fungi account for about 60% of total marine microbial new natural products and the most studied genera are Aspergillus and Penicillium [22][12].
A bisabolane-type sesquiterpenoid, (−)-sydonic acid (16), was isolated from marine-derived fungus Aspergillus sp. associated with the sponge Xestospongia testudinaria (Figure 2). Compound 16 exhibited significant inhibiting activity against V. Parahaemolyticus and V. anguillarum with MIC values of 10.0 and 5.00 μM[23][13]. A new polyketide, asperochrin A (17), was isolated from Aspergillus ochraceus MA-15, which was isolated from the rhizospheric soil of marine mangrove plant Bruguiera gymnorrhiza. Compound 17 displayed significant antibacterial activity against A. hydrophilia, V. anguillarum and V. harveyi, with MIC values of 8 μg/mL, 16 μg/mL and 8 μg/mL, respectively [24][14]. A new prenylated phenol derivative, terreprenphenol A (18), was isolated from Aspergillus terreus EN-539, which was obtained from the marine red alga Laurencia okamurai. Compound 18 displayed potent activity against A. hydrophila, P. aeruginosa, and V. harveyi with MIC values of 2, 2, and 4 μg/mL, respectively [25][15].
Figure 2. Structures of marine Aspergillus-derived compounds against aquatic pathogenic bacteria, (−)-sydonic acid (16), asperochrin A (17), terreprenphenol A (18), ent-aspergoterpenin C (19), 7-O-methylhydroxysydonic acid (20), hydroxysydonic acid (21), aspewentin D (22), aspewentin F (23), aspewentin G (24), aspewentin H (25), aspewentin A (26), aspewentin I (27), aspewentin J (28), seco-clavatustide B (29), clavatustide B (30), aspergixanthone I (31), 3-((1-hydroxy-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)methyl)-1-methyl-3,4-dihydrobenzo[e][1,4]diazepine-2,5-dione (32), austalide R (33), 4-methyl-3”-prenylcandidusin A (34), questin (35), trypacidin (36), 7β,8β-epoxy-(22E,24R)-24-methylcholesta-4,22-diene-3,6-dione (37), and ergosta-4, 6, 8(14), 22-tetraene-3-one (38).
Two new bisabolane-type sesquiterpenoid derivatives, ent-aspergoterpenin C (19) and 7-O-methylhydroxysydonic acid (20), and a known bisabolane sesquiterpenoid, hydroxysydonic acid (21), were isolated from the deep-sea sediment-derived fungus Aspergillus versicolor SD-330. Compound 19 exhibited antibacterial activities against E. tarda, P. aeruginosa, V. harveyi, and V. parahaemolyticus with MIC value of 8.0 μg/mL. Compound 20 exhibited antibacterial activities against E. tarda, V. anguillarum, A. hydrophilia, V. harveyi, and V. parahaemolyticus with MIC value of 8.0 μg/mL. Compound 21 exhibited more potent activities against A. hydrophilia, E. tarda, V. anguillarum and V. harveyi with MIC value of 4.0 μg/mL [26][16].
Four new 20-nor-isopimarane diterpenoids, aspewentins D, F, G and H (22–25), and a known congener, aspewentin A (26), were isolated from the deep-sea sediment-derived Aspergillus wentii SD-310. Compounds 22–26 showed inhibitory activity against the aquatic pathogens M. luteus, E. tarda, V. harveyi, P. aeruginosa, and V. parahemolyticus with MIC value of 4.0 μg/mL [27][17]. Meanwhile, two uncommon 20-nor-isopimarane diterpenoid epimers, aspewentin I (27) and aspewentin J (28) were also isolated from A. wentii SD-310. Compounds 27 and 28 showed antibacterial activities against E. tarda, V. harveyi, and V. parahaemolyticus with MIC value of 8.0 μg/mL [28][18].
Two aminobenzoic peptide, seco-clavatustide B (29) and clavatustide B (30), were characterized from the Ascidian-derived endophytic fungus Aspergillus clavatus AS-107. Compounds 29 exhibited potent activity against A. hydrophilia, with a MIC value of 8.2 μM, while compound 30 showed antibacterial activity against P. aeruginosa, with a MIC value of 8.8 μM [29][19]. A new prenylxanthone derivative, aspergixanthone I (31), was isolated from the marine-derived fungus Aspergillus sp. ZA-01. Compound 31 showed the strongest antibacterial activity against V. parahemolyticus (MIC = 1.56 μM), V. anguillarum (MIC = 1.56 μM) and V. alginolyticus (MIC = 3.12 μM) [30][20].
A new tryptophan derived alkaloid, 3-((1-hydroxy-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)methyl)-1-methyl-3,4-dihydrobenzo[e][1,4]diazepine-2,5-dione (32), and a new meroterpenoid, austalide R (33), were isolated from the fungus Aspergillus sp., isolated from the Mediterranean sponge Tethya aurantium. Compound 32 showed significant antibacterial activities against V. harveyi and V. natriegens, with MIC value of 1 μg/mL. Compound 33 displayed the better potential activity against V. harveyi with a MIC value of 0.1 μg/mL [31][21]. A prenylcandidusin derivative, 4-methyl-3”-prenylcandidusin A (34), was isolated from the coral-derived fungus Aspergillus tritici SP2-8-1. Compound 34 displayed stronger antibacterial activities against strains of V. vulnificus, V. rotiferianus, and V. campbellii, with MIC values ranging from 7 to 15 μg/mL [32][22].
Bioassay-guided fractionation resulted in the isolation of an antibacterial compound against V. harveyi, questin (35), from the marine-derived Aspergillus flavipes strain HN4-13. Compound 35 exhibited the same anti-V. harveyi activity as streptomycin sulfate (MIC 31.25 μg/mL) [1][23]. Trypacidin (36) was isolated from Aspergillus fumigatus HX-1 associated with Clams. Compound 36 showed the same anti-V. harveyi activity as streptomycin sulfate, with a MIC value of 31.25 µg/mL [33][24]. 7β,8β-epoxy-(22E,24R)-24-methylcholesta-4,22-diene-3,6-dione (37) and ergosta-4, 6, 8(14), 22-tetraene-3-one (38) were steroids isolated from the deep sea-derived fungus Aspergillus penicillioides SD-311. Compound 37 showed antibacterial activity against V. anguillarum with MIC value of 32.0 µg/mL. Compound 38 exhibited inhibitory activity against E. tarda and M. luteus, with MIC value of 16 μg/mL [34][25].
3. Marine Penicillium
Two new phenolic bisabolane sesquiterpenes, peniciaculins A (39) and B (40), a new nor-bisabolane derivative, 1-hydroxyboivinianin A (41), and a known bisabolene, (7S,11S)-(+)-12-hydroxysydonic acid (42), were isolated from the deep-sea sediment-derived Penicillium aculeatum SD-321 (Figure 3). Compound 39 exhibited antibacterial activity against V. alginolyticus with MIC value of 2.0 μg/mL, while compounds 40 and 41 showed inhibitory activity against E. tarda and V. harveyi, with MIC values of 8.0 and 4.0 μg/mL, respectively. Compound 42 exhibited significant antibacterial activity against V. parahemolyticus, with MIC value of 0.5 μg/mL[35][26].
Figure 3. Structures of marine Penicillium-derived compounds against aquatic pathogenic bacteria, peniciaculin A (39), peniciaculin B (40), 1-hydroxyboivinianin A (41), (7S,11S)-(+)-12-hydroxysydonic acid (42), adametizine A (43), pyranonigrin F (44), pyranonigrin A (45), chermesin A (46), chermesin B (47), chermesiterpenoid B (48), chermesiterpenoid C (49), (3S,4S)-sclerotinin A (50), citrinin H2 (51), 20-acetoxy-7-chlorocitreorosein (52), 9-dehydroxysargassopenilline A (53), 1,2-didehydropeaurantiogriseol E (54), penicisimpin A (55), penicisimpin B (56), penicisimpin C (57), and penicillilactone A (58).
A new bisthiodiketopiperazine derivative, adametizine A (43), was isolated from marine-sponge derived fungus Penicillium adametzioides AS-53. Compound 43 showed antibacterial activities against A. hydrophilia, V. harveyi and V. parahaemolyticus, with MIC values of 8, 32, and 8 μg/mL, respectively [36][27]. A new polyAS-53-dione derivative, pyranonigrin F (44), and a related known compound, pyranonigrin A (45), were isolated from an endophytic fungus Penicillium brocae MA-231, which was obtained from the fresh tissue of the marine mangrove plant Avicennia marina. Compounds 44 and 45 displayed significant activity against V. harveyi and V. parahaemolyticus with MIC values of 0.5 μg/mL [37][28].
Two new spiromeroterpenoids, chermesins A (46) and B (47), were isolated from an endophytic fungus Penicillium chermesinum EN-480, which was isolated from the inner tissue of the marine red alga Pterocladiella tenuis. Compounds 46 and 47 displayed significant activity against M. luteus, with MIC value of 8 μg/mL [38][29]. Meanwhile, two new sesquiterpenoids, chermesiterpenoids B (48) and C (49), were isolated from P. chermesinum EN-480. Compound 48 and 49 exhibited antibacterial activities against V. anguillarum, V. parahaemolyticus and M. luteus, with MIC values of 0.5, 16, and 64 μg/mL, and 1, 32, and 64 μg/mL, respectively [39][30].
(3S,4S)-sclerotinin A (50) and citrinin H2 (51) were isolated from the deep sea-derived fungus Penicillium citrinum NLG-S01-P1. Compounds 50 and 51 displayed relatively stronger activities against V. vulnificus and V. campbellii, with MIC values ranging from 15 to 17 μg/mL, respectively [40][31]. A new chlorinated metabolite, 20-acetoxy-7-chlorocitreorosein (52), was isolated from Penicillium citrinum HL-5126, an endophytic fungus that was isolated from the mangrove Bruguiera sexangula var. rhynchopetala collected in the South China Sea. Compound 52 exhibited antibacterial activity against V. parahaemolyticus, with a MIC value of 10 μM [41][32]. Two new polyketide derivatives, 9-dehydroxysargassopenilline A (53) and 1,2-didehydropeaurantiogriseol E (54), were isolated from the deep sea-derived fungus Penicillium cyclopium SD-413. Compounds 53 and 54 exhibited inhibitory activities against E. tarda, M. luteus, V. anguillarum, and V. harveyi, with MIC values ranging from 4 to 32 μg/mL [42][33].
Three new dihydroisocoumarin derivatives, penicisimpins A–C (55–57), were isolated from Penicillium simplicissimum MA-332, a fungus that was isolated from the rhizosphere of the marine mangrove plant Bruguiera sexangula var. rhynchopetala. Compounds 55–57 exhibited broad-spectrum inhibitory activities with various MIC values ranging from 4 to >64 mg/mL, with compound 55 showing highest activities against P. aeruginosa, V. parahaemolyticus, and V. harveyi, with MIC value of 4 μg/mL, while compounds 56 and 57 exhibited moderate activities against the tested strains [43][34]. One novel 7-membered lactone derivative, penicillilactone A (58), was isolated from the sponge-derived fungus Penicillium sp. LS54. Compound 58 showed antibacterial activity against V. harveyi, with a MIC value of 8 μg/mL [44][35].