Antibacterial Molecules from Marine Microorganisms against Aquatic Pathogens: A Concise Review

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. This review is aimed to make a comprehensive survey of anti-aquatic pathogenic bacterial compounds that were produced by marine microorganisms. A total of 79 compounds have been reported, covering literature from 1997 to 2021. The compounds are included in different structural classes such as polyketides, terpenoids, nitrogen compounds and others, and some of them present the potential to be developed into agents for the treatment of aquatic pathogenic bacteria.


Introduction
With the rapid and intensive development of aquaculture, many problems related to aquatic animal diseases and environmental pollution of the water body have gradually been exposed, which has seriously restricted the stable development of aquaculture [1]. The main pathogens of aquatic animals include bacteria, viruses and parasites etc. [2]. It is estimated that China's annual losses caused by aquatic animal diseases are more than 10 billion yuan. Among them, the economic loss of aquatic animal caused by bacterial diseases accounts for 58%, which is the most serious factor leading to the economic loss of aquaculture [3].
Major bacterial pathogens are Vibrio, Aeromonas, Edwardsiella, Flavobacterium, Pseudomonas, and Micrococcus. Vibrio is the most important class of pathogens for bacterial diseases in marine aquaculture. Vibriosis has the characteristics of widespread area and high incidence. The common pathogenic Vibrio spp. in aquaculture includes Vibrio anguillarum, Vibrio harveyi, Vibrio parahaemolyticus, and Vibrio alginolyticus. V. anguillarum is the earliest studied pathogen with high pathogenicity to fish, and the symptom of infection is mainly sepsis. V. harveyi is a light-emitting bacterium and a main pathogen of aquatic animals, especially in the nursery and growing stages of shrimp [1]. The main symptoms of V. harveyi infection in fish are subcutaneous hemorrhage, redness of the anus, and sides of the skull. V. parahaemolyticus can cause inflammation and congestion on the surface of shrimp and marine fish, such as acute hepatopancreatic necrosis disease [4].
Aeromonas hydrophila is the main pathogen in the genus Aeromonas. Fish infected with A. hydrophila are prone to fulminant bleeding disorders, such as erythematosus of carp and loach, and "printing disease" (rotten skin) of catfish [5]. Edwardsiella tarda and Edwardsiella ictaluri are the most common aquatic pathogens in the genus Edwardsiella. E. tarda and E. ictaluri have been found in a variety of farmed freshwater and marine fish, such as eel, flounder, rainbow trout, and catfish. The disease caused by E. tarda or E. ictaluri is known as enteric septicemia of catfish (ESC) [6]. In addition, yellow mullet, black bass, goldfish, mullet can also be infected.
Flavobacterium columnare is a common pathogenic bacterium in the family Flavobacteriaceae, and usually attacks the skins, fins and gills of fish. The disease caused by F. columnare is often called "columnaris disease" [7]. The symptoms of disease are basically the same, including severe necrosis of gill tissue and skin ulceration from systemic infection. The pathogens of the genus Pseudomonas causing fish diseases are mainly Pseudomonas aeruginosa and Pseudomonas fluorescens etc. Pseudomonas can cause diseases in a variety of aquatic animals, such as hemorrhagic, red skin, rot skin, and ulcer diseases [8]. Micrococcus luteus is the main cause of hemorrhagic disease in Monopterus albus. After infection, the symptoms are diffuse bleeding on the surface, anal swelling and eversion of the anus, and cause high mortality [9].
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 [10]. Therefore, it is urgent to develop new antibacterial agents for aquatic products.
Bio-derived drugs have the advantages of relatively safe, low toxicity, and easy degradation. They are ideal for finding safe and harmless antibacterial raw materials for the aquatic application. At present, marine microorganisms are an important resource for the development of antibacterial agents used in aquaculture. This review article outlines various anti-aquatic pathogenic bacterial molecules produced from marine microorganisms. The availability of these compounds will help develop various applications in the aquaculture field of antibiotics against aquatic bacterial pathogens.

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].
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]. 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]. Tirandamycins A (14) and B (15) were isolated from the crude extract of Streptomyces tirandamycinicus sp. nov., a novel marine sponge-derived actinobacterium.

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].

Concluding Remarks and Future Prospects
Since Cephalosporins were isolated from the secondary metabolites of marine-derived fungus Acremonium chrysogenum in 1945, especially since the 1990s, more than 20,000 inspirational natural products with diverse structures and potential bioactivities have been discovered in marine microbes [55]. From our literature review, although marine microbial secondary metabolites have been shown to have diverse biological activities [11,56], there are relatively few reports evaluating their antibacterial activity against aquatic pathogens . Among the 79 active molecules against aquatic bacterial pathogens, there are only 15 compounds derived from marine bacteria, accounting for 19%. In contrast, antibacterial compounds derived from marine fungi accounted for more than 80%, and were isolated mainly from two genera Aspergillus (23, 29%) and Penicillium (20, 25%) ( Figure 5). When it comes to structural classes, polyketides, terpenoids and nitrogencontaining compounds are the three major structural types of marine microbial-derived anti-aquatic pathogenic bacterial active molecules, accounting for 57%, 25%, and 15%, respectively ( Figure 6). containing compounds are the three major structural types of marine microbial-derived anti-aquatic pathogenic bacterial active molecules, accounting for 57%, 25%, and 15%, respectively ( Figure 6).  As reported in this review, some marine microbial-derived natural products have good potential against aquatic bacterial pathogens, but there are very few in-depth reports of the in vivo antibacterial efficacy and safety of active molecules [20]. Therefore, further research should focus on the in vivo bacteriostatic effect and safety of marine microbialderived active compounds against aquatic pathogens in this field.
At present, a limited number of reports on the mechanism of action of anti-aquatic pathogenic active compounds have focused on the changes in bacterial morphology, the inhibition of growth, and the damage in cell membrane and cell wall [13,16,57]. More research is needed to study the mechanism of action of the compounds at the molecular or genetic level. containing compounds are the three major structural types of marine microbial-derived anti-aquatic pathogenic bacterial active molecules, accounting for 57%, 25%, and 15%, respectively ( Figure 6).  As reported in this review, some marine microbial-derived natural products have good potential against aquatic bacterial pathogens, but there are very few in-depth reports of the in vivo antibacterial efficacy and safety of active molecules [20]. Therefore, further research should focus on the in vivo bacteriostatic effect and safety of marine microbialderived active compounds against aquatic pathogens in this field.
At present, a limited number of reports on the mechanism of action of anti-aquatic pathogenic active compounds have focused on the changes in bacterial morphology, the inhibition of growth, and the damage in cell membrane and cell wall [13,16,57]. More research is needed to study the mechanism of action of the compounds at the molecular or genetic level.  As reported in this review, some marine microbial-derived natural products have good potential against aquatic bacterial pathogens, but there are very few in-depth reports of the in vivo antibacterial efficacy and safety of active molecules [20]. Therefore, further research should focus on the in vivo bacteriostatic effect and safety of marine microbial-derived active compounds against aquatic pathogens in this field.
At present, a limited number of reports on the mechanism of action of anti-aquatic pathogenic active compounds have focused on the changes in bacterial morphology, the inhibition of growth, and the damage in cell membrane and cell wall [13,16,57]. More research is needed to study the mechanism of action of the compounds at the molecular or genetic level.
In conclusion, based on the huge demand for environmentally friendly antibiotic alternatives in the aquaculture industry, further research should deeply evaluate the antibacterial efficacy and safety of marine microbial active molecules in vivo, and investigate their mechanism of action.
Author Contributions: Writing-original draft preparation, S.G. and Z.Z.; writing-review and editing, L.G.; funding acquisition, L.G. All authors have read and agreed to the published version of the manuscript.