Type: Review article

Natural antibacterial compounds from aquatic animals for controlling fish pathogenic bacteria: Mechanisms, efficacy, and prospects for sustainable aquaculture

Mohamed Ashour ¹, Roshmon Thomas Mathew ¹, M. Moshiur Rahman ², Einar Ringø ³

^1.         Fish Resources Research Center, King Faisal University, Hofuf-420, Al-Ahsa 31982, Saudi Arabia

^2.         Department of Biological and Agricultural Engineering, University of California, Davis, Davis, CA 95616, USA

^3.         Faculty of Biosciences, Fisheries, and Economics, Norwegian College of Fishery Science, UiT The Arctic University of Norway, Tromsø, Norway

Corresponding author: Mohamed Ashour; E-mail: mashour@kfu.edu.sa

Abstract

Aquaculture faces escalating bacterial disease burdens and mounting antimicrobial resistance (AMR) driven by intensive production and extensive antibiotic use, threatening animal health, productivity, and One Health security. This review synthesizes current knowledge on natural antibacterial compounds derived from aquatic animals, with a primary focus on antimicrobial peptides (AMPs) and related metabolites from finfish, crustaceans, mollusks, echinoderms, gastropods, cnidarians, and other invertebrates. After outlining the global status of major Gram-negative and Gram-positive fish and shellfish pathogens, their infection routes, and the limitations of conventional control measures, the review critically examines skin mucus, serum and organ factors, hemolymph-derived AMPs, tissue lectins, and non protein bioactives such as chitin, chitosan, and carotenoids. Particular emphasis is placed on cationic, α helical AMPs (≈350 reported from aquatic invertebrates) that exhibit broad-spectrum activity against Vibrio spp., Aeromonas spp., Streptococcus spp., Staphylococcus aureus, Escherichia coli, and Salmonella through membrane disruption, intracellular targeting, and immunomodulation, often with lower resistance propensity than conventional antibiotics. Less conventional sources, including echinoderms, gastropods, and cnidarians, are highlighted for their structurally diverse peptides, saponins, and microbiome-derived metabolites that show promising in vitro and in vivo efficacy and compatibility with saline environments. The review further discusses omics driven discovery, bioinformatics-guided peptide design, and biotechnological production (recombinant systems, synthetic analogs, and valorization of processing by products) as key enablers for scale up and standardization. Finally, major challenges—variability of natural sources, cost, regulatory hurdles, safety, and environmental fate—are evaluated alongside research and policy priorities needed to translate aquatic-animal-derived antibacterials into integrated, commercially viable tools for sustainable, antibiotic sparing aquaculture.

Keywords

Antimicrobial peptides; Aquatic invertebrates; Fish bacterial diseases; Sustainable aquaculture; Antibiotic alternatives

Submitted: 24-01-2026;    Revised: 02-03-2026;         Accepted: 29-03-2026;      Online: 31-03-2026

Cite as: Ashour, M., Mathew, R. T., Rahman, M. M.., & Ringø, E. (2026). Natural antibacterial compounds from aquatic animals for controlling fish pathogenic bacteria: Mechanisms, efficacy, and prospects for sustainable Aquaculture: Early View. Animal Reports, 2(1), 105-139. https://doi.org/10.64636/ar.46

1           Introduction

One of the significant constraints to the sustainable development of the aquaculture industry may be regarded as the impact of bacterial diseases, and they should be addressed with the help of useful practices (Vijayaram et al., 2024). The resulting effect of such reliance on conventional antibiotic treatment in terms of both outcomes is the irreversible rates of antimicrobial resistance and the emission of greenhouse gases and the need to find an ecologically-friendly solution (Julyantoro et al., 2024). This has initiated a significant exploration of natural compounds particularly those of aquatic organisms, which have got potential properties, such as biodegradability, reduced resistance formation and better safety profiles (Naiel et al., 2023).

Extensive research has characterized the structural diversity and general bioactivities of seaweed polysaccharides, including sulfated galactans (carrageenans), fucoidans, and alginates from red, brown, and green macroalgae (Ciancia et al., 2020). However, critical knowledge gaps persist regarding their targeted antibacterial efficacy against aquaculture-specific pathogens. Most studies focus on broad-spectrum activity against human or terrestrial pathogens (e.g., S. aureus, E. coli), with limited data on fish/vibriosis-relevant species such as Vibrio harveyi, Aeromonas hydrophila, and Streptococcus iniae. Structure-activity relationships (SAR) remain underexplored, particularly how sulfation patterns, molecular weight, and monosaccharide composition influence pathogen selectivity and minimum inhibitory concentrations (MICs) (Sule et al., 2025)

The review will give a synthesis of available knowledge on natural antibacterial compounds that have been identified in different aquatic organisms and their ability to act against the common aquaculture pathogens, as well as their mechanism of action. Specifically, this paper will review both in vitro and in vivo evidence that supports the application of these compounds in finfish, crustaceans, and mollusks in controlling the critical bacterial pathogens that impact the aquaculture of finfish and shellfish (Elgendy et al., 2024). This will include the discussion of the structural classes, target pathogens and the proposed modes of action of the said compounds in detail. It will also be addressed in terms of the less traditional resources, such as echinoderms and cnidarians, and their bioactive metabolites, which are specific and potentially can interact synergistically with the already existing treatment(s) (Van Doan et al., 2023). It has been reviewed against the background of the increased issue of antibiotic resistance and reviews the therapeutic and health benefits of these natural compounds as demonstrated alternatives to conventional antibiotics in aquaculture. This review is set against the backdrop of the growing problem of antibiotic resistance, and examines the therapeutic and health advantages of these natural compounds as proven alternatives to traditional antibiotics in aquaculture. This would be consistent with the growing need to implement sustainable aquaculture practices, which are undermined by frequent disease outbreaks resulting in significant economic losses (Elgendy et al., 2024).

Natural compounds (e.g., phytotherapeutics, probiotics, antimicrobial peptides, etc.) exploration can be used as a complex solution to these losses by enhancing the immune system of fishes and directly attacking the pathogen (Pandey et al., 2025). In fact, bioactive compounds added to aquaculture are one of the promising approaches to dwelling on sustainability and product quality (Tekam et al. 2025). As the transfer of antimicrobial resistance genes and resistant bacteria between the aquatic environment and terrestrial environment is a global issue of concern, alternative sources of natural antibiotics should be explored as a solution to sustainability. The review will mainly concentrate on compounds that have been identified and characterised to give modern knowledge on promising phytocompounds and marine based compounds which can successfully overcome antimicrobial resistance (Rahimi et al., 2022). Additionally, the existing literature on the area of natural antibacterial compounds extracted by finfish, crustaceans, mollusks, and other aquatic invertebrates regarding their efficacy and possible use in aquaculture will be thoroughly evaluated in the context of counteracting the growing trend of antimicrobial resistance (Bhat et al., 2024). Specifically, antimicrobial peptides of various aquatic organisms are one of the promising categories of alternatives, as they have a broad range of antimicrobial action, and their likelihood of causing resistance is also lower than that of traditional antibiotics (Wang et al., 2023). Their varied modes of action including membrane disruption and immunomodulation provide an alternative approach to disease control that avoids much of the problems there are with conventional chemotherapeutics (Naiel et al., 2023).

2           Background and Theory

2.1         Fish Pathogenic Bacteria and Disease Load

The aquaculture industry suffers great economic loss and welfare challenges in the global market across a large spectrum of bacterial pathogens affecting finfish and shellfish (Naiel et al., 2023). These are the pathogens such as representatives of the genera Aeromonas, Vibrio, Streptococcus, Flavobacterium, and Edwardsiella, among others, which are infamous in causing high morbidity and mortality rates in farmed aquatic organisms (Rahimi et al., 2022). These bacterial infections have a devastating economic effect, which in most cases would result in poor feed conversion, reduced growth rates, and the total loss of stock, thus posing a risk to the sustainability of the aquaculture business across the world. Moreover, mass production of such outbreaks using traditional antibiotics has worsened the problem of antimicrobial resistance and several studies have reported the rise of resistant strains of bacteria in aquaculture facilities (Syahidah et al., 2015). Such resistance not only threatens the effectiveness of well-known treatment methods but also presents a significant risk to the human condition due to the possible introduction of resistance genes into human pathogens (Abdel-Latif et al., 2023). To give examples, Edwardsiella ictaluri isolates of striped catfish in Vietnam have been shown to be resistant to streptomycin, with the increasing resistance trends also shown in strains of Aeromonas veronii (Syahidah et al., 2015). The existing control methods, such as vaccines and improved husbandry practices, are not sufficient to prevent massive outbreaks, which is why they must find new, long-term, sustainable therapeutic solutions (Pourmozaffar et al., 2025). The increasing nervousness also highlights the necessity of creating and implementing appropriate risk reduction strategies that rely on a One Health approach, involve harsh antimicrobial usage prescriptions, stricter biosecurity, and antibiotic-substitutes (Milijasevic et al., 2024). Massive, non-selective antibiotic use in fish farming, and most notably in the developing world, has played a major role in the development of antimicrobial resistance, owing to the lack of sanitary soundness in fish farming and the subsequent selective forces to the bacterial population (Syahidah et al., 2015).

Most disease outbreaks are caused by bacterial pathogens, which account for 54.9% of all outbreaks and pose a serious risk to the health of fish in aquaculture activities, with both socioeconomic consequences, including decreased production and income loss (Alfatat et al., 2025). The economic effect is also increased by the fact that the market value of diseased fish is reduced, the cost of doing business rises due to treatment interventions, and the effects are felt over the long term in terms of trade and food security (Elgendy et al., 2024). The widespread use of antimicrobial agents to control disease, particularly after stressful events such as handling and transportation, unintentionally drives the evolution of antimicrobial resistance, thereby reducing treatment efficacy and continuing economic losses (da Costa et al., 2021). This intensive use of antibiotics has contributed to an epidemic of antimicrobial resistance worldwide, and investigations in the Lao PDR have found that a sizeable fraction of fish farms use antibiotics to treat conditions such as streptococcosis, and special operations reported the highest antimicrobial dependence (Tayyab et al., 2025). The growing resistance is not only harming the health of aquatic organisms but also posing a risk of spreading resistance genes into the environment, including clinical environments (Sule et al., 2025). In turn, the development of alternative methods and techniques of controlling pathogenic bacteria is the most important, especially since the losses incurred by global shrimp farming today in terms of pathogenic diseases is more than 40% of its potential (Julyantoro et al., 2024)

Furthermore, the advent of multidrug-resistant E. coli isolates in cultured fish, which host resistance genes, such as blaTEM and blaCTX, suggests that it is time to change the approach to preventive microbial education to generate resilient and health-promoting microbiomes as early developmental stages (Tayyab et al., 2025). The latter frightening trend highlights the dire need to engage in a concerted international initiative to discover and deploy sustainable alternatives to traditional antibiotics in fish farming (Hegde et al., 2023). The losses to the economy due to fish diseases are considerable, with references to 100 million USD of losses due to summer mortality in tilapia farms in Egypt and 11.1 million USD/year losses in commercial catfish farms in West Alabama, showing the great urgency behind the establishment of effective disease management strategies (Elgendy et al., 2024)

The economic damages caused by pathogens like Vibrio parahaemolyticus and Streptococcus agalactiae, among others, may be over a billion dollars annually in economic costs due to the diseases in aquaculture, and their annual losses could be US6 billion globally (Tayyab et al., 2025). This is further complicated by the ubiquitous occurrence of antibiotic resistance genes in aquaculture environments, including extended-spectrum b-lactamases and quinolone resistance genes, which complicate the management of diseases and require new, innovative methods in place of conventional antimicrobials (Milijasevic et al., 2024). Nevertheless, the constant abuse of antimicrobials in aquaculture has also resulted in a tremendous rise of antibiotic-resistant bacteria and resistance genes, as the prevalence of beta-lactam, tetracycline, and fluoroquinolone resistance in Gram-negative bacteria is high, and the presence of mobile genetic elements that promote the spread of resistance (Debnath et al., 2025). Such a worrying trend requires the immediate identification and adoption of long-term solutions to the traditional use of antibiotics to address the increasing concern of antimicrobial resistance in aquaculture (Elgendy et al., 2024)

2.2         Global status of bacterial diseases in aquaculture and economic impact

Bacterial diseases are a significant challenge to the evolutionary development of the aquaculture industry, resulting in significant losses (more than 40 percent) of global capacity, particularly in shrimp cultivation. The reason is mainly because of the harsh rearing conditions found in the aquaculture sector where transmission and growth of pathogens take place within a short period, resulting in a high mortality rate and massive financial losses (Julyantoro et al., 2024). These diseases cause the world to incur an estimated US 6 billion yearly and developing countries are over-represented in this problem, frequently losing up to 50 percent of an aquaculture crop to bacterial infections (Fabrikov et al., 2024). Because of their wide distribution and the capacity to capitalize on host weaknesses during periods of stress, bacterial pathogen loads are commonplace and cause severe epizootics, which only adds to the economic cost to aquaculturists (Defoirdt et al., 2011). In particular, bacterial diseases are the leading cause of losses in aquaculture, often comprising more than 83 per cent, and is a significant impediment to the projected expansion of the sector to surpass the level of the wild-catch production by 2028 (Elgendy et al., 2024). Antibiotics have also been widely used in aquaculture to prevent these bacterial menaces, but to unintended effects, it has resulted in the mass production of antimicrobial resistance, making it a major problem of sustainable disease control (Rajan et al., 2023). This disturbing tendency requires a unified action to work out alternative therapeutic approaches, effective against virulent strains of bacteria and environmentally friendly (Gravningen et al., 2019). Antimicrobial peptides are especially emerging as a potential alternative to other options because they are broad spectrum antimicrobials and have the potential to activate host immunity (Naiel et al., 2023). The innate immune system of most organisms of which the endogenous peptides have become an attractive strategy to minimize high economic and welfare barriers of bacterial diseases in aquaculture has become a viable strategy to offer an environmentally friendly and sustainable disease management plan (Akhavan-Bahabadi et al., 2024). This issue of mounting has shown the importance of creative solutions in the area of aquaculture where antimicrobial peptides are the primary focus of active research on the basis of which they can potentially be substituted with the use of traditional antibiotics (Kim, 2018).

They have a clear-cut advantage over conventional antibiotics because of their unique modes of action, including membrane permeabilization and immunomodulation, which avoids the activation of the well-known resistance mechanisms and enhances the host defense (Saeed et al., 2022)). They tend to possess a high bactericidal rate and have a lower tendency to develop resistance, which is why these peptides are the best options in terms of overcoming the long-standing issue of bacterial diseases in aquaculture (García-Beltrán et al., 2023). Moreover, the complicated interaction between possible fish pathogens, host biology, and the environment is essential in the development of the holistic disease prevention and control strategies (Hegde et al., 2023). By accepting the complexity of disease susceptibility, this review will outline the type of pathogenic bacteria that are common in aquaculture, their economic and welfare effects. Such pathogens are a wide range of Gram-negative and Gram-positive bacteria, which together lead to high morbidity, mortality, and therefore cause significant challenges to the sustainability and growth of the global aquaculture industry (Tayyab et al., 2025). This section will also be a critical review on the available control measures such as antibiotics, vaccines, and animal husbandry highlighting their weaknesses in the effort to curb the burden of the disease and indicating that they need new solutions as soon as possible (Defoirdt et al., 2011).

2.3         Limitations of Conventional Antibiotics and Emergence of Antimicrobial Resistance

The widespread use of conventional antibiotics in the aquaculture industry in the context of prophylaxis, metaphylaxis, and treatment has been associated with some limitations, the main ones being the rapid development of antimicrobial resistance in some of the most common bacterial pathogens—Vibrio spp., Aeromonas spp., and Edwardsiella spp. (Reverter et al., 2020). Selective pressure is caused by indiscriminate use, commonly accumulated through intensive agricultural techniques and poor biosecurity, which selectively favors the survival and expansion of resistant strains through mechanisms such as plasmid-mediated horizontal gene transfer and integrons (Debnath et al., 2025).

As an example, amoxicillin, ampicillin, and erythromycin resistance was observed in more than 80 percent of V. harveyi isolates in Italian finfish farms, and multidrug resistance is common in Asian aquaculture systems, which are associated with high rates of antibiotic usage (Bhat & Altinok, 2023). This exacerbates the effectiveness of treatment, deepens the severity of an outbreak, and continues to loss over US$6 billion a year in lost productivity and escalated costs of intervention (Elgendy et al., 2024). The crisis is further aggravated by environmental persistence of antibiotics and resistance genes, which pollute sediments, water, and wild populations and turn into reservoirs of zoonotic transfer to human pathogens (Reverter et al., 2020).

According to meta-analyses, the indices of multi-antibiotic resistance in low and middle-income countries are high and are associated with warmer temperatures and prophylactic administration, which endangers the health of people through the food chain (Schar et al., 2021). Regulatory trade barriers and consumer health issues are also caused by residues in edible fish tissues, highlighting the unsustainability of the existing practices (Ferri et al., 2022). Such restrictions indicate the pressing necessity of alternatives, not only because of their ineffectiveness against the resistant pathogens, but also due to their disturbance of microbial ecosystems and the selection of hyper-virulent strains (Elgendy et al., 2024).

This increasing quandary has given way to a strategic shift to more innovative and sustainable approaches to disease control such as vaccines, probiotics, bacteriophages, and antimicrobial peptides in a bid to curb the large-scale propagation of antimicrobial resistance (Li & Sun, 2017). To meet this dire need, the aquaculture industry is paying much attention to the natural compounds of aquatic species as a possible and sustainable alternative to the traditional antibiotics because of their multiple structures and broad-spectrum antimicrobial activity (Bhat & Altinok, 2023).These compounds have clear benefits such as biodegradability, reduced chances of developing resistance, and greater safety profiles of both farmed organisms and the environment and are extremely appealing to reduce the impact of bacterial diseases in aquaculture without contributing to the ongoing issue of antimicrobial resistance (Sanches-Fernandes et al., 2022). This strategy goes right to the root of the urgent need to minimize the use of conventional antimicrobials by utilizing the natural defense systems that have been developed in aquatic organisms.

3           Major Bacterial Pathogens in Aquaculture

3.1         Overview of key Gram-negative and Gram-positive fish and shellfish pathogens

Bacterial pathogens represent a primary threat to aquaculture production worldwide, with Gram-negative species predominating over Gram-positive ones in causing disease outbreaks, morbidity, and mortality across finfish, crustaceans, and mollusks (Hegde et al., 2023). Such pathogens are subjected to intensive farming which is enhanced by high levels of stocking, low water quality and environmental stressors causing significant economic losses (Alfatat et al., 2025).

Key Gram-negative pathogens include Vibrio spp. (e.g., V. harveyi, V. vulnificus), which cause vibriosis—a systemic infection affecting marine fish and shrimp with symptoms like hemorrhages, ulcers, and high mortality (Mohamad et al., 2019; Zhang et al., 2020; Manchanayake et al., 2023); Aeromonas spp. (e.g., A. hydrophila, A. salmonicida), responsible for hemorrhagic septicemia and furunculosis in freshwater and marine fish (Бакиев & Бисенбаев, 2021); Edwardsiella piscicida (formerly E. tarda), etiological agent of edwardsiellosis in over 20 fish species (Buján et al., 2018); Tenacibaculum maritimum, causing tenacibaculosis with ulcerative lesions, fin rot, and tail erosion in marine fish (Mabrok et al., 2023); Photobacterium damselae (photobacteriosis); Pseudomonas spp.; and Flavobacterium columnare (columnaris disease) (Sansone et al., 2022; Hegde et al., 2023).

Gram-positive pathogens, though less prevalent, include Streptococcus spp. (e.g., S. iniae, S. agalactiae), inducing streptococcosis with meningoencephalitis and septicemia in tilapia, salmonids, and sea bass (Mishra et al., 2018; Gnanagobal & Santander, 2022; Haenen et al., 2023); Lactococcus garvieae; Renibacterium salmoninarum (bacterial kidney disease in salmonids); Nocardia seriolae (nocardiosis); and Staphylococcus spp. (Gnanagobal & Santander, 2022; Fabrikov et al., 2024). Table 1 summarizes prominent pathogens, their characteristics, affected hosts, and associated diseases.

Table 1. Key bacterial pathogens of cultured fish species and their associated diseases

There is a need for targeted alternatives like antimicrobial peptides to combat these pathogens amid rising antimicrobial resistance (Hegde et al., 2023). Beyond these, other significant Gram-negative bacteria contributing to disease burden include Flavobacterium psychrophilum (coldwater disease), F. branchiophilum (bacterial gill disease), Edwardsiella ictaluri (enteric septicemia of catfish), and Yersinia ruckeri (enteric redmouth disease) (Aziz & Abdullah, 2021). Additionally, Gram-negative species such as Aliivibrio salmonicida and Photobacterium damselae are well-documented causes of bacterial diseases in aquaculture, contributing to substantial morbidity and economic losses (Bondad-Reantaso et al., 2020; Manan et al., 2023).

Vibrio is a genus of bacteria that includes some of the most pathogenic species, including Vibrio anguillarum, Vibrio parahaemolyticus, and Vibrio vulnificus that are often involved in serious outbreaks of aquaculture in the marine ecosystem (Bondad-Reantaso et al., 2020). Although Gram-negative infections are clearly more common, Gram-positive pathogens are also very damaging, and Streptococcus iniae, Streptococcus agalactiae, Lactococcus garvieae, and Renibacterium salmoninarum, are especially problematic with most aquaculture species (Bhat & Altinok, 2023). Although being of different Gram staining, these bacterial infections often cause high fatality and considerable financial losses in the sphere of aquaculture at the global level (Hegde et al., 2023). As an example, Aeromonas motile species are the most frequent cause of infection in freshwater aquaculture and bring about skin ulcers, fin lesions, and systemic septicemia, whereas Vibrio species are the cause of rampant hemorrhagic septicemia in both cold and freshwater (Wickramanayake et al., 2023). The intensive agriculture methods related to the development of the aquaculture business provide an environment favorable to the emergence of such bacterial outbreaks because of the density of fish and related stress (Hudecová et al., 2023). Aeromonas hydrophila is a significant warmwater bacterium, and its cold-water counterpart Aeromonas salmonicida are known to cause a variety of diseases in different aquatic organisms, such as hemorrhagic septicemia and furunculosis (Gotesman et al., 2018). The other prominent Gram-negative bacteria like Pseudomonas spp. and Yersinia spp. are also known to contribute to disease outbreak and are especially associated with shrimp aquaculture resulting in high mortality rate, thereby causing severe economic losses (Ali et al., 2022). The high economic cost of the bacterial diseases requires the consideration of sustainable and efficient ways to contain them instead of traditional antibiotics, with the growing concerns of antimicrobial resistance (Maldonado-Miranda et al., 2022; Santos et al., 2023). Annual economic losses in the global aquaculture industry are estimated to be US$6 billion because of these bacterial pathogens, with contrary to viral and parasitic etiologies, all disease outbreaks are caused by bacteria (Alfatat et al., 2025).

3.2         Infection routes, clinical signs, and impacts on farmed species

Horizontal transfer through infected water is the primary pathway of entry of bacteria pathogens into aquaculture, and the sources of entry include damaged skin, gills, fins, and the gastrointestinal tract as a result of host ingestion of contaminated food or water (Mohamad et al., 2019; Rasmussen, 2019; Anjur et al., 2021). Vertical transmission is not as common but there are cases that it occurs. Increased stocking density, low water quality, and change in temperature are the stress factors that make it susceptible (Dinçtürk et al., 2018; Hudecová et al., 2023). Vibrio spp. (e.g., V. harveyi, V. anguillarum) can infect marine fish and shrimp through skin wounds, gills, and fins and through the mouth cavity, especially in larvae when it spreads into the bloodstream via endocytosis of the intestine (Dinçtürk et al., 2018; Manchanayake et al., 2023). In shrimps, clinical manifestations are hemorrhages, skin lesions, gastroenteritis, eye damage, muscle necrosis, fin/tail rot, and luminous vibriosis (Mohamad et al., 2019; Zhang et al., 2020; Sanches-Fernandes et al., 2022). The morbidity is up to 50-100% with outbreaks, which is also adding billions of annual losses to the world (Sony et al., 2021; Stabili et al., 2022). Aeromonas spp. (e.g., A. hydrophila, A. salmonicida) invades through gills, abrasions of the skin and through fins, and grows successfully in stress (Anjur et al., 2021; Abdella et al., 2024). The manifested symptoms include hemorrhagic septicemia, furunculosis, ulcers, fin rot, ascites, and organ necrosis, and the mortality rate is up to 80-100 percent (Hegde et al., 2023). Edwardsiella piscicida enters through water exposure and injuries and causes septicemia-based Edwardsiellosis (Buján et al., 2018). The transmission of Tenacibacillum maritimum is waterborne, whereby the pathogen attaches itself to epithelial surfaces and induces lesions that are characterized by Tenacibaculosis comprising of epidermal ulcers, mouth erosion, fin necrosis, and tail rot; lesions are usually complicated by other secondary invaders such as Vibrio spp (Mabrok et al., 2023). There is a high rate of mortality of marine species. S. iniae, S. agalactiae, and Streptococcus spp. (S. iniae and S. agalactiae) are transmitted through waterborne routes, contaminated feed, direct/handling contact, and are responsible for causing salmonids, sea bass, and tilapia (Haenen et al., 2023). The symptoms are lethargy, unstable swimming, exophthalmia, hemorrhages, meningoencephalitis, and septicemia, and outbreaks lead to 20-100% fatality (Abu‐Elala et al., 2020). The same situation occurs with Lactococcus garvieae that causes hemorrhages and exophthalmia in yellowtail and trout (Gnanagobal & Santander, 2022). These infections are estimated to cause approximately 55 percent of disease outbreak, causing US dollar 6-billion annual losses due to mortality and low growth (Alfatat et al., 2025). Knowledge of these pathways is essential to devise specific prophylactic strategies and therapeutic approaches to reduce the disease course and negative economic impact in aquaculture. The knowledge of these pathways is essential to devise specific prophylactic strategies and therapeutic approaches to reduce the disease course and negative economic impact in aquaculture (Mohamad et al., 2019). Table 2 gives a brief description of the most significant bacterial pathogens of cultured fish, which summarises their modes of entry into the host, their main clinical presentation, and mortality and economic consequences.

Table 2. Major bacterial pathogens in aquaculture: infection routes, clinical signs, and economics

Pathogen	Infection routes	Primary clinical signs	Impacts (mortality/economic)	References
Vibrio spp. (e.g., V. harveyi, V. anguillarum)	Skin, gills, fins, oral (especially larvae via intestinal endocytosis)	Hemorrhages, skin ulcers, fin/tail rot, gastroenteritis, eye lesions, luminous vibriosis in shrimp	50–100% mortality; outbreaks associated with substantial global economic losses (billions USD)	(Sanches-Fernandes et al., 2022; Stabili et al., 2022)
Aeromonas spp. (e.g., A. hydrophila, A. salmonicida)	Skin abrasions, gills, fins	Hemorrhagic septicemia, ulcers, furunculosis, fin rot, ascites, internal organ necrosis	80–100% mortality in severe outbreaks; major cause of production losses	(Maldonado-Miranda et al., 2022; Abdella et al., 2024)
Edwardsiella piscicida	Water contact, skin wounds	Septicemia (edwardsiellosis)	Significant disease problem affecting more than 20 cultured fish species	(Buján et al., 2018)
Tenacibaculum maritimum	Waterborne infection, attachment to epithelial surfaces	Epidermal ulcers, mouth erosion, fin and tail necrosis/rot	High mortalities in marine fish; lesions often complicated by secondary invaders such as Vibrio spp	(Mabrok et al., 2023)
Streptococcus spp. (e.g., S. iniae, S. agalactiae)	Waterborne transmission, contaminated feed, direct contact, handling	Lethargy, erratic swimming, exophthalmia, hemorrhages, meningoencephalitis, septicemia	20–100% mortality; major constraint in tilapia and other warm‑water species	(Haenen et al., 2023; Sule et al., 2025)

3.3 Current control measures and their constraints

Current strategies to manage bacterial diseases in aquaculture primarily rely on antibiotics, vaccines, probiotics, biosecurity measures, and emerging alternatives like phage therapy, though each faces significant limitations (Aly et al., 2024; Elgendy et al., 2024). Antibiotics such as oxytetracycline, florfenicol, and erythromycin are commonly administered via feed or water to treat outbreaks of Vibriosis, Aeromoniasis, and Streptococcosis; however, their overuse has led to widespread antimicrobial resistance in pathogens like Vibrio spp., Aeromonas hydrophila, and Streptococcus agalactiae, alongside environmental contamination and residues in aquaculture products posing risks to human health (Sanches-Fernandes et al., 2022; Bhat & Altinok, 2023).

Vaccination is a viable prophylaxis method that is sustainable, and it is efficient against Streptococcus spp. (e.g. lowers mortality in tilapia), Vibrio spp., and Aeromonas spp. in salmonids and seabass and is delivered through vaccination as inactivated or live vaccines (e.g., by injection, immersion, or feed) (Elgendy et al., 2024; Sule et al., 2025). Strain-specific, autogenous vaccines to farm-specific strains have potential to develop fast-evolving pathogens such as Streptococcus, although they face the challenges of strain variability, limited cross-protection, high costs to develop, logistical barriers to administration (particularly of larvae/shrimp), and lack of coverage across species (Bhat & Altinok, 2023). Probiotics (e.g., beneficial Vibrio or Lactobacillus strains), prebiotics and synbiotics increase host immunity, gut health and competitive exclusion of pathogens, decreasing the need of antibiotics in shrimp and finfish (Sanches-Fernandes et al., 2022; Aly et al., 2024). Biosecurity measures, such as quarantine, equipment disinfection, maximum stocking densities, and water quality management, stop the introduction and horizontal transmission but must be strictly followed, which is difficult in intensive systems (Aly et al., 2024; Elgendy et al., 2024). Narrow-spectrum bacteriophage therapy against specific bacteria (Aeromonas hydrophila and Vibrio harveyi) can be used instead, which avoids the risk of AMR, whereas phytotherapeutics and immunostimulants are used in supportive roles (Hossain et al., 2023; Elgendy et al., 2024). Nevertheless, phages do not propagate, have stability, and cost problems; probiotics are not uniform in their effect; and all this needs additional validation in the field (Elias et al., 2023). These have addressed some of the losses, yet AMR, economic pressures and intensification demonstrate the desperate need to build integrated sustainable solutions to protect the productivity of aquaculture (Aly et al., 2024; Elgendy et al., 2024). Regardless of the progress, the use of single-mode interventions may not be effective enough, and it is important to consider multi-faceted approaches, especially the ones that utilize natural compounds with a wide spectrum of action and immunomodulatory effects (Hegde et al., 2023). This scenario puts a stake on the necessity to explore alternatives, including bacteriocins, quorum quenying, and biosurfactants, which may offer good prospects of controlling the disease without fuelling the antibiotic resistance (Elgendy et al., 2024). Table 3 summarizes the principal control measures used in aquaculture to manage bacterial diseases, highlighting their target pathogens, typical efficacy, and key practical constraints in field application.

3.3         Cross-Compound Efficacy Comparison

Comparative analysis of antibacterial efficacy across seaweed-derived compounds reveals distinct patterns in pathogen selectivity and potency. Phlorotannins demonstrate superior activity against Gram-negative Vibrio species, achieving minimum inhibitory concentrations (MICs) of 4-16 μg/mL against V. harveyi and V. parahaemolyticus, the most economically significant aquaculture pathogens (Pradhan et al., 2022). In contrast, sulfated peptides exhibit optimal efficacy against Gram-positive streptococci (S. iniae, L. garvieae) with MICs of 8-32 μg/mL, making them ideal candidates for warm-water aquaculture systems where streptococcosis predominates.Alkaloids from Caulerpa and Sargassum species show intermediate potency (MIC 16-64 μg/mL) but provide broad-spectrum coverage across both Gram-positive and Gram-negative pathogens, particularly Edwardsiella tarda and Photobacterium damselae (Heckman, 2021).

Steroids, while exhibiting higher MIC values (32-128 μg/mL), demonstrate bactericidal rather than bacteriostatic action, with MBC/MIC ratios consistently below 2, indicating rapid cell death mechanisms via membrane permeabilization.Pathogen-specific optimization emerges from this cross-compound analysis: V. harveyi infections respond optimally to phlorotannins and lipid fractions, Aeromonas hydrophila to peptide-alkaloid combinations, while Streptococcus iniae outbreaks require sulfated polysaccharide formulations. These differential activity spectra enable evidence-based compound selection aligned with regional disease challenges and dominant pathogen profiles in specific aquaculture production systems. (Jeong et al., 2023).

Table 3. Current Control Strategies Against Bacterial Diseases in Aquaculture.

Measure	Targeted pathogens	Efficacy	Constraints	References
Antibiotics	Vibrio spp., Aeromonas spp., Streptococcus spp.	High short‑term control of active infections	Development of antimicrobial resistance, drug residues, and environmental pollution	(Bhat & Altinok, 2023)
Vaccines	Streptococcus spp., Vibrio spp., Aeromonas spp.	50–90% reduction in mortality in vaccinated stocks	Strain specificity, administration and delivery challenges, relatively high costs	(Elgendy et al., 2024)
Probiotics/Prebiotics	Mainly Vibrio spp., Aeromonas spp.	Enhanced immune response and reduced outbreak frequency	Variable efficacy among farms and products; need for regulatory approval and standardization	(Ali et al., 2022; Sanches-Fernandes et al., 2022)
Biosecurity	Broad spectrum (all pathogens)	Prevents introduction and spread of infectious agents	Implementation and compliance can be difficult in intensive systems	(Manan et al., 2023; Elgendy et al., 2024)
Phage therapy	Aeromonas hydrophila, Vibrio harveyi	Highly specific lysis with low tendency for resistance	Production and formulation costs, stability and shelf‑life constraints	(Hossain et al., 2023; Elgendy et al., 2024)

4           Natural Compounds from Finfish

4.1         Skin Mucus‑Derived Compounds

Examples include fatty acids, triglycerides, and other lipid molecules found in the skin and mucus. The skin mucus-derived compounds, such as fatty acids, triglycerides, and other lipid molecules, are fatty acids, triglycerides, and lipids. Fish skin mucus is the main physical and chemical barrier in the innate immune system of finfish, which has a wide range of bioactive compounds, including antimicrobial peptides, lysozymes, lectins, histones, glycoproteins, proteases, and immunoglobulins that offer broad-spectrum protection against bacterial pathogens such as Vibrio spp., Aeromonas hydrophila, Streptococcus spp., and Tenacibaculum maritimum common in aquaculture. These components derived by mucus are characterized by strong antibacterial, antifungal, and antiviral activity due to their mechanism of action such as disrupting cell membrane, lysis, and competitive exclusion, which makes them promising antibiotic alternatives in overcoming antimicrobial resistance in farmed finfish, including tilapia, salmon, seabass, and seabream (Lirio et al., 2019; Tiralongo et al., 2020; Bhatnagar & Rathi, 2021). For example, epidermal mucus extracts from tilapia, catfish, and snakehead showed potent anti-aquaculture activity against pathogenic organisms such as A. hydrophila and human-relevant pathogens such as Pseudomonas aeruginosa and Klebsiella pneumoniae, in many instances equivalent to broad-spectrum antibiotics (Lirio et al., 2019). Histone H2A-derived parasin I of catfish, piscidins of cod, and oncorhyncin II of rainbow trout are notable AMPs that have no hemolytic activity against Gram-positive or Gram-negative bacteria (Dash et al., 2018; Yang et al., 2022). Although it is variable depending on species, stress and environment, through the use of all three types of mucus extraction (aqueous, acidic, organic), prophylactic applications such as feed additives or baths can be isolated at scale, making it worthwhile to further test in vivo to integrate mucus in aquaculture (Tiralongo et al., 2020; Sansone et al., 2022; Díaz-Puertas et al., 2023). In particular, the active secretion and shedding of epidermal mucus imply that pathogens must locate an upstream path through an unstirred layer, a physical mechanism that prevents the stable colonization and invasion of infectious microorganisms (Jurado et al., 2015). The natural barrier is further reinforced by the wide repertoire of different antimicrobial compounds present in the mucus, including a-helical peptides of the piscidins and defensins type, generated out of inactive precursors and functioning by destabilizing cell membranes or by binding to microbial DNA to prevent replication (Santoso et al., 2020). Moreover, this defense is also greatly supported by lysozyme and pleurocidin which is also present in fish mucus, and catfish mucus tends to have better inhibitory capabilities against Gram-positive microorganisms such as Staphylococcus aureus and Micrococcus luteus. The mechanism of action that is observed when Gram-positive bacteria are targeted by a particular activity of some fish mucus extracts, i.e., catfish mucus, is commonly related to the essence of antimicrobial action performed by identified lysozyme and pleurocidin (Lirio et al., 2019). Also, it has been shown that Amphiprion clarkii mucus has a strong antibacterial effect against Gram-negative bacteria and antiparasitic effect, whereas Epinephelus tauvina mucus is a strong antimicrobial agent against human and fish pathogens, especially Vibrio parahaemolyticus (Tiralongo et al., 2020). This pan-microbial antimicrobial effect emphasizes the possibility of designing new therapeutic agents on the basis of fish epidermal mucus and providing a substitute to traditional antibiotics in aquaculture (Santoso et al., 2020). Since the ecological heterogeneity and the stress response changes the mucus composition, additional studies are essential to equalize the extraction and characterization methods to guarantee the same effectiveness and safety of the therapeutic (Lirio et al., 2019; Santoso et al., 2020). Furthermore, an intricate relationship between environmental variables, species-specific responses of fish, and dynamics of microbial communities inside the aquatic environment will be of paramount importance in the maximization of production and use of these mucus-based compounds in commercial aquaculture systems. This would be a systematic way of transferring laboratory results to a real-world scenario on large scale application of such natural antimicrobials in disease prevention and control measures in the aquaculture industry (Hussain & Sachan, 2023). Enlightening the entire molecular processes and synergies of the different mucus components are also a research that should be done in the future in order to fully exploit the therapeutic potential of these compounds (Hussain & Sachan, 2023). Table 4 highlights representative antimicrobial molecules identified in fish skin mucus, emphasizing their finfish sources, principal target pathogens, and modes of action relevant to aquaculture disease control.

 Table 4. Key Antimicrobial molecules Derived from Fish Skin Mucus

Compound/peptide	Finfish species	Target pathogens	Main antimicrobial activity/mechanism	Reference
Parasin I (histone H2A fragment)	Amur catfish (Silurus asotus)	Gram‑positive and Gram‑negative bacteria; fungi	Membrane disruption leading to rapid cell death	(Dash et al., 2018)
Piscidins	Cod (Gadus spp.)	Broad range of bacteria	Pore formation and lysis of microbial cell membranes	(Dash et al., 2018)
Oncorhyncin II	Rainbow trout (Oncorhynchus mykiss)	Gram‑positive and Gram‑negative bacteria	Broad‑spectrum bactericidal activity without hemolysis	(Yang et al., 2022)
Lysozyme, lectins, proteases	Tilapia, salmon, seabass	Vibrio spp., Aeromonas spp., Streptococcus spp.	Enzymatic lysis of cell walls, agglutination, proteolysis	(Tiralongo et al., 2020; Hussain & Sachan, 2023)
Glycoproteins and various AMPs (e.g., pleurocidin‑like peptides)	Catfish, snakehead	Aeromonas hydrophila, Staphylococcus aureus	Growth inhibition, especially of Gram‑positive bacteria	(Lirio et al., 2019)

4.2         Serum, Plasma, and Organ-Derived Factors

In finfish, serum and plasma form an important part of humoral defense mechanisms and contain antimicrobial proteins and peptides, including lysozymes, complement components, C-reactive protein, hepcidins, histones, and piscidins that provide defense against aquaculture pathogens, such as Aeromonas hydrophila, Streptococcus agalactiae, Vibrio spp., and Streptococcus iniae common in fish species like tilapia, salmon, and rainbow trout(Charlie- These circulating factors have broad-spectrum antibacterial effects due to a range of mechanisms, such as enzymatic lysis, opsonization, agglutination, membrane permeabilization, and immunomodulation, which offer viable antibiotic alternatives to the increase in antimicrobial resistance in farmed finfish (Bo et al., 2019; Akhavan-Bahabadi et al., 2024; Barroso et al., 2025). As an illustration, Nile tilapia CRP increases monocyte/macrophage phagocytosis and exhibits calcium-dependent bacterial agglutination of S. agalactiae and A. hydrophila, whereas tilapia calreticulin regulates inflammatory reactions and phagocytosis (Yin et al., 2020; Li et al., 2022). Dynamic immune remodeling is demonstrated by the upregulation of acute-phase proteins such as complement C3 and alpha-2-macroglobulin in rainbow trout plasma after infection or immunization (Causey et al., 2018; Bakke et al., 2020; Morro et al., 2020). The organ-derived compounds, especially liver and spleen compounds, contain hepcidins, a family of cysteine-rich peptides that are mainly produced in hepatocytes, and have high Gram-positive and Gram-negative bacterial activity, but are not hemolytically toxic (Yang et al., 2022; Barroso et al., 2025). Histone H1 fragments of coho salmon serum enhance the action of pleurocidin, whereas post-Aeromonas salmonicida challenge liver proteomes indicate complement activation and metabolic changes (Causey et al., 2018; Yang et al., 2022). Non-lethal plasma sampling and organ extraction procedures can be used to isolate aquaculture prophylactics such as immunostimulants or therapeutic using RNA-based methods despite its effects on infection status, species, and environment, and require in vivo validation (Katzenback, 2015; Akhavan-Bahabadi et al., 2024). Acute-phase reactants produced by the liver like ceruloplasin and haptoglobin becomes surge during A. hydrophila infection in tilapia, which is associated with granulocyte influx and elimination of bacteria (Charlie-Silva et al., 2019). This systemic immunity supplements the epidermal barriers, and CRP and complement produce opsonins to label invaders in order to be phagocytosed and hepcidins chelate iron to starve the bacteria (Li & Sun, 2017; Li et al., 2022). Rainbow trout plasma possesses direct antibacterial actions, which can be ascribed to proteomics of multifacetedness, entailing AMPs and proteases (Mizaeva et al., 2023). Commercialization of these factors will be maximized by leveraging omics strategies to conduct widespread profiling to alleviate disease in high-density farming (Bakke et al., 2020; Morro et al., 2020). The table below (Table 5) highlights key humoral antimicrobial proteins and peptides identified in finfish serum, plasma, and organs, underscoring their sources, target pathogens, and mechanisms relevant to aquaculture disease management.

Table 5. Serum, Plasma, and Organ-Derived Antimicrobial Factors from Finfish

Compound/protein	Source (tissue/fluid)	Finfish species	Target pathogens	Main activity/mechanism	Reference
CRP (C-reactive protein)	Serum	Nile tilapia (Oreochromis niloticus)	S. agalactiae, A. hydrophila	Calcium-dependent agglutination; enhances phagocytosis	(Li et al., 2022)
Complement C3	Plasma	Tilapia, rainbow trout	Broad range of bacteria	Opsonization and membrane lysis	(Causey et al., 2018; Charlie-Silva et al., 2019)
Hepcidin	Liver/serum	Trout, salmon	Gram-positive and Gram-negative bacteria	Iron sequestration, membrane disruption	(Barroso et al., 2025)
Histone H1 (fragments)	Serum	Coho salmon (Oncorhynchus kisutch)	Aquaculture pathogens	Immunomodulation, synergy with other AMPs	(Yang et al., 2022)
Lysozyme	Plasma	Salmonids (Salmo salar, etc.)	Gram-positive and Gram-negative bacteria	Enzymatic hydrolysis of peptidoglycan	(Katzenback, 2015)
Calreticulin	Serum	Nile tilapia	Bacteria	Phagocytosis promotion, inflammation modulation	(Yin et al., 2020)
Alpha-2-macroglobulin	Plasma	Rainbow trout (Oncorhynchus mykiss)	Pathogenic bacteria	Protease inhibition, acute-phase immune response	(Bakke et al., 2020)

 

5           Natural Compounds from Crustaceans

5.1         Hemolymph-Derived Antibacterial Factors

Hemolymph in crustaceans serves as a critical humoral component of the innate immune system, abundant in antimicrobial peptides and proteins such as penaeidins, crustins, anti-lipopolysaccharide factors, lysozymes, stylicins, and hemocyanins, providing defense against prevalent aquaculture pathogens including Vibrio harveyi, V. parahaemolyticus, V. alginolyticus, Aeromonas hydrophila, and Gram-positive bacteria in species like black tiger shrimp, whiteleg shrimp, and mud crab (Fredrick & Ravichandran, 2012; Banerjee et al., 2015; Aweya et al., 2021; Elbahnaswy et al., 2025). These agents mediate broad-spectrum antimicrobial effects through membrane permeabilization, LPS neutralization, enzymatic lysis, agglution, opsonization, and prophenol oxidase activation and are promising antibiotic alternatives to crustacean farming in the face of antimicrobial resistance (Aguirre-Guzman et al., 2009; Li et al., 2019). An example is penaeidins of prawn granulocyte, which has a strong antifungal and Gram-positive antibacterial effect and anti-inflammatory effect, and recombinant crustins of P. monodon, which possess strong activity in inhibiting Vibrio pathogens with MICs of 0.5 mg/ml (Banerjee et al., 2015; Elbahnaswy et al., 2025). ALFs are first discovered in horseshoe crabs and found in shrimp hemocytes, which bind LPS to suppress Gram-negative bacteria and fungi, and isoforms such as LvALF1 increase resistance in the case of knockdowns reversed (Jiang et al., 2022). Post-V. harveyi or V. alginolyticus challenge proteomic studies of hemocytes indicate the up-regulation of hemocyanin, prophenoloxidase, and serine proteases among P. monodon and S. paramamosain (Somboonwiwat et al., 2010; Sun et al., 2017). Although it is variable because of infection, species and stressors, non-lethal hemolymph sampling with arthrotomy would provide scalable extraction of aquaculture prophylactics and therapeutics with in vivo efficacy trials required (Aguirre-Guzman et al., 2009; Fredrick & Ravichandran, 2012). The peptides of the hemocyanin of L. vannamei exhibit extensive non-toxic activity and supplement cellular defense mechanisms such as phagocytosis (Sun et al., 2017). Post-exposure omics profiling reveals dynamic changes in proteomics, which are useful in the discovery of biomarkers (Somboonwiwat et al., 2010; Sun et al., 2017). These AMPs can be harnessed by recombinant production or immunostimulants to sustain crustacean aquaculture and the focus of future efforts should be on molecular pathways, immunomodulator synergies, and standardisation to remain commercially viable (Banerjee et al., 2015; Aweya et al., 2021).

Table 6 summarizes prominent hemolymph-derived antimicrobial factors from crustaceans, highlighting their sources, target aquaculture pathogens, and primary modes of action for potential therapeutic applications.

 

Table 6. Key Hemolymph-Derived Antimicrobial Peptides and Proteins from Crustaceans

Compound/protein	Source (cells/tissue)	Crustacean species	Target pathogens	Main activity/mechanism	Reference
Penaeidins	Granulocytes/hemocytes	Black tiger shrimp (P. monodon), whiteleg shrimp (L. vannamei)	Gram‑positive bacteria, fungi	Membrane permeabilization, anti‑inflammatory	(Banerjee et al., 2015; Elbahnaswy et al., 2025)
Crustins	Hemocytes	P. monodon, L. vannamei	Vibrio spp. (V. harveyi, V. alginolyticus), A. hydrophila	Gram‑negative inhibition (MIC 0.5 μg/ml), LPS neutralization	(Banerjee et al., 2015; Elbahnaswy et al., 2025)
Anti-LPS factors (ALFs)	Hemocytes	Shrimp (L. vannamei), mud crab (S. paramamosain)	Gram‑negative bacteria (V. parahaemolyticus), fungi	LPS binding, endotoxin neutralization	(Li et al., 2019; Jiang et al., 2022)
Lysozymes	Hemolymph	Shrimp, mud crab	Gram‑positive and Gram‑negative bacteria	Enzymatic cell wall hydrolysis	(Fredrick & Ravichandran, 2012; Aweya et al., 2021)
Stylicins	Hemocytes	Shrimp	Bacteria	Membrane disruption	(Fredrick & Ravichandran, 2012; Aweya et al., 2021)

5.2         AMPs and Lectins from Shrimp and Crabs

Lectins and additional AMPs from tissues such as hepatopancreas, gills, and intestine in shrimps and crabs function as pattern recognition receptors and direct antimicrobials, complementing hemolymph defenses against aquaculture pathogens like Vibrio parahaemolyticus, V. harveyi, Aeromonas hydrophila, and white spot syndrome virus (Fredrick & Ravichandran, 2012; Wang et al., 2020; Aweya et al., 2021; Rodrigues et al., 2025). C-type lectins recognize pathogen-associated molecular patterns including LPS, peptidoglycan, and β-glucans, promoting agglutination, opsonization, phagocytosis, proPO activation, and sometimes bacterial clearance or AMP regulation (Runsaeng et al., 2017; Wang et al., 2020). For instance, dual-CRD FmLC6 from banana shrimp hepatopancreas binds diverse bacteria and viruses, while mannose-specific rFmLC3 exhibits direct antimicrobial activity against Vibrio spp. (Runsaeng et al., 2017; Runsaeng et al., 2018). PvML1 in whiteleg shrimp hemocytes specifically binds LPS to suppress V. parahaemolyticus via AMP upregulation (Wang et al., 2022). Penaeidins 3/5 and crustin isoforms from granules/tissues show potent Gram+/- inhibition (Banerjee et al., 2015; Wu et al., 2019). Sparanegtin has extensive antibacterial effects in mud crabs (Zhu et al., 2021). Infection status, environmental stressor, and species-specific variability notwithstanding, recombinant expression and tissue profiling can be scaled to produce aquaculture therapeutics, and omics studies have found synergies and post-challenge upregulation (Sun et al., 2017; Tao et al., 2019; Rodrigues et al., 2025). In vivo validation and standardization will enhance their deployment as antibiotic alternatives in sustainable shrimp and crab farming (Wang et al., 2020; Aweya et al., 2021).

Table 7 presents key lectins and antimicrobial peptides isolated from crustacean tissues beyond hemolymph, illustrating their roles in recognizing and combating aquaculture pathogens through pattern recognition and direct antimicrobial effects.

 Table 7. Tissue-Derived Lectins and AMPs from Shrimp and Crabs

Compound/protein	Source (tissue)	Crustacean species	Target pathogens	Main activity/mechanism	Reference
FmLC6 (dual-CRD C-type lectin)	Hepatopancreas	Banana shrimp (Fenneropenaeus merguiensis)	Diverse bacteria, white spot syndrome virus (WSSV)	Pathogen binding, agglutination, immune modulation	(Runsaeng et al., 2018)
FmLC3 (mannose-specific lectin)	Hepatopancreas	Banana shrimp (F. merguiensis)	Vibrio spp., Gram‑positive/negative bacteria	Direct antimicrobial, bacterial agglutination	(Runsaeng et al., 2017)
PvML1 (mannose-binding lectin)	Hemocytes	Whiteleg shrimp (Litopenaeus vannamei)	V. parahaemolyticus	LPS recognition, upregulation of AMPs	(Wang et al., 2022)
Penaeidin 3/5	Granulocytes	Banana shrimp (F. merguiensis)	Gram‑positive and Gram‑negative bacteria	Membrane permeabilization and disruption	(Wu et al., 2019)
Crustin isoforms	Hemocytes	Black tiger shrimp (Penaeus monodon)	Vibrio spp., Gram‑positive/negative bacteria	Broad‑spectrum bacterial inhibition	(Banerjee et al., 2015)
Sparanegtin	Multiple tissues	Mud crab (Scylla paramamosain)	Broad range of bacteria	Direct antimicrobial, immunoprotective	(Zhu et al., 2021)
MjCTL3/4 (C-type lectins)	Hemocytes	Kuruma shrimp (Marsupenaeus japonicus)	WSSV, V. parahaemolyticus	Pathogen binding, antibacterial activity	(Zhang et al., 2020)

5.3         Other Crustacean-Derived Bioactives

Beyond proteinaceous AMPs and lectins, crustacean exoskeletons, shells, heads, and viscera yield non-protein bioactives such as chitin, chitosan, carotenoids (e.g., astaxanthin), and polyunsaturated fatty acids with antimicrobial, antioxidant, and immunostimulatory properties against aquaculture pathogens including Vibrio spp. and WSSV (Hamed et al., 2016; Rossi et al., 2024). Chitosan from shrimp shell waste disrupts bacterial membranes via positive charge interactions, inhibits Gram-positive/negative bacteria, and enhances shrimp immunity as a feed additive (Vilar Junior et al., 2016; Mohan et al., 2019; Mittal et al., 2021).

Astaxanthin from shells/hepatopancreas scavenges reactive oxygen species, bolsters antioxidant defenses, and improves disease resistance in L. vannamei (Rossi et al., 2024). Chitin and derivatives act as prebiotics modulating gut microbiota, while PUFAs support membrane integrity and anti-inflammatory responses (Olatunde et al., 2020). Despite extraction challenges from variable waste composition, scalable bioprocessing of shells and by-products via fermentation or chemical methods enables sustainable production of these bioactives as antibiotic alternatives in shrimp/crab feeds (Hamed et al., 2016; Tanganini et al., 2020; Resmi et al., 2021). Omics analyses post-supplementation reveal upregulated antioxidant enzymes and microbiota shifts, underscoring synergies with innate defenses for commercial aquaculture viability (Mohan et al., 2019).

The table below (Table 8) outlines key non-protein bioactives derived from crustacean exoskeletons, shells, and viscera, emphasizing their antimicrobial, antioxidant, and immunostimulatory roles against aquaculture pathogens.

Table 8. Non-Protein Bioactive Compounds from Crustacean By-Products

Compound/class	Source (by-product)	Crustacean species	Target pathogens/effects	Main activity/mechanism	Reference
Chitosan	Shells/exoskeleton	Whiteleg shrimp (L. vannamei), black tiger shrimp (P. monodon)	Gram‑positive/negative bacteria	Positive charge-mediated membrane disruption; immunostimulant	(Hamed et al., 2016; Vilar Junior et al., 2016; Mittal et al., 2021)
Chitin	Exoskeleton waste	Penaeid shrimp (Penaeus spp.), mud crab (S. paramamosain)	Bacteria, fungi	Prebiotic modulation of gut microbiota; direct antimicrobial	Hamed et al., 2015; Mohan et al., 2018
Astaxanthin	Shells, hepatopancreas	Whiteleg shrimp (L. vannamei)	Vibrio spp., oxidative stress	ROS scavenging, enhanced disease resistance	Doan et al., 2023; Rossi et al., 2024
Polyunsaturated fatty acids (PUFAs)	Viscera, heads	Penaeid shrimps, crabs	Inflammatory/pathogenic bacteria	Anti-inflammatory, membrane integrity support	Doan et al., 2023; Olatunde et al., 2020
Carotenoids (e.g., astaxanthin derivatives)	Shell waste	Black tiger shrimp (P. monodon)	WSSV, bacteria	Immunomodulation, antioxidative protection	Doan et al., 2023; Rossi et al., 2024

6           Natural Compounds from Mollusks

6.1         Bivalve‑Derived Antibacterial Peptides and Proteins

Lectins and additional AMPs from tissues such as hemocytes, mantle, gills, and digestive gland in bivalves like oysters and mussels function as pattern recognition receptors and direct antimicrobials, complementing hemolymph defenses against aquaculture pathogens like Vibrio splendidus, V. anguillarum, and ostreid herpesvirus 1 (Bachère et al., 2015; Canesi et al., 2022; Canesi & Pruzzo, 2016; Destoumieux‐Garzón et al., 2020). C-type lectins and galectins recognize pathogen-associated molecular patterns including LPS, peptidoglycan, and β-glucans, promoting agglutination, opsonization, phagocytosis, and antimicrobial regulation (Smits, 2019; Wang et al., 2017). For instance, big defensin Cg-BigDef1 from Pacific oyster hemocytes assembles into antimicrobial nanonets entrapping Vibrio spp. and other bacteria (Bachère et al., 2015; Canesi et al., 2022), while hemocyte defensins Cg-Defh1/2 inhibit Gram+/- bacteria via peptidoglycan biosynthesis disruption (Bachère et al., 2015; Ulagesan et al., 2022). Mytilin and myticin from mussel hemocytes/granules exhibit broad inhibition against Vibrio spp. and Gram+/- bacteria (Destoumieux‐Garzón et al., 2020; Novoa et al., 2016; Yang et al., 2021). Regardless of species-specific variability, infection status, and environmental stressors, recombinant expression and tissue profiling allow scalable production of aquaculture therapeutics, omics studies display synergies and post-challenge upregulation (Bachere et al., 2015; Nguyen and Alfaro, 2019; Rodrigues et al., 2025). Their deployment in the vivo as alternatives to antibiotics in sustainable bivalve farming will be improved through in vivo validation and standardization (Naiel et al., 2023). Other AMPs and in particular lectins and other tissues like hemocytes, mantle, gills, and digestive gland in bivalves like oysters and mussels can be recognized as pattern recognition receptors and complementary antimicrobials to hemolymph defenses against aquaculture pathogens such as Vibrio splendidus, V. anguillarum and ostreid herpesvirus 1. Lectins of C-type and galectins identify pathogen associated molecular patterns such as LPS, peptidoglycan and b-glucans, stimulating agglutination, opsonization, phagocytosis and antimicrobial control (Destoumieux-Garzon et al., 2020; Naiel et al., 2023).

Table 9 summarizes key lectins and AMPs characterized in representative bivalve species, highlighting their tissue sources, major targets, and predominant activities relevant to aquaculture health management.

 

Table 9. bivalve-derived lectins and antimicrobial peptides (AMPs), their tissue sources, main target pathogens, and principal activities relevant to aquaculture health management.

Compound/Protein	Source	Bivalve species	Target pathogens	Activity	Reference
Cg-BigDef1	Hemocytes	Crassostrea gigas	Vibrio spp., Gram+/− bacteria	Nanonet entrapment, potent antibacterial	(Bachère et al., 2015; Canesi et al., 2022)
Cg-Defh1/2	Hemocytes	Crassostrea gigas	Gram+/− bacteria	Peptidoglycan inhibition, antimicrobial	(Bachère et al., 2015; Ulagesan et al., 2022)
Cg-Defm	Mantle	Crassostrea gigas	Gram+/− bacteria	Membrane disruption	(Bachère et al., 2015)
Mytilin	Hemocytes	Mytilus galloprovincialis	Vibrio splendidus, V. anguillarum	Broad-spectrum inhibition	(Destoumieux-Garzon et al., 2020; Yang et al., 2021)
Myticin C	Hemocytes	Mytilus galloprovincialis	Gram+/− bacteria, OsHV-1	Antimicrobial, antiviral	(Novoa et al., 2016)
Myticusin-beta	Hemocytes	Mytilus coruscus	Gram+/− bacteria	Antibacterial	(Oh et al., 2020)
Myticalin	Gills/hemocytes	Mytilus galloprovincialis	Bacteria	Antimicrobial	(Canesi et al., 2022)

6.2         Gastropod-Derived Metabolites

Gastropod mollusks such as abalone and sea snails yield bioactive metabolites including hemocyanin-derived antimicrobial peptides, viscera hydrolysates, mucus glycoproteins, and plasma proteins with antibacterial, antiviral, cytotoxic, and immunomodulatory activities against aquaculture pathogens like Vibrio spp. and viruses (Green et al., 2015; Rivera-Pérez et al., 2023; Watson et al., 2022; Zhuang et al., 2014). Hemocyanin functional units in Haliotis tuberculata release haliotisin peptides that inhibit Gram-positive and Gram-negative bacteria via α-helical structures disrupting membranes (Zhuang et al., 2014). Viscera-derived peptides from Haliotis fulgens and H. corrugata exhibit antimicrobial effects, while skin mucus from Bolinus brandaris demonstrates potent cytotoxicity and immune activation (Rivera-Pérez et al., 2023; Sansone et al., 2022). Broad-spectrum plasma proteins from gastropod hemolymph show antiviral potential against herpesviruses (Green et al., 2015; Watson et al., 2022).

Despite extraction challenges from variable tissue composition and lower research compared to bivalves/crustaceans, enzymatic hydrolysis of viscera/waste and recombinant expression enable scalable production for aquaculture feeds, enhancing disease resistance as shown in abalone vibriosis trials (Chen et al., 2020; Rivera-Pérez et al., 2023). Omics profiling post-supplementation reveals immune gene upregulation, supporting their viability as sustainable antibiotic alternatives (Green et al., 2015; Zhuang et al., 2014).

Additional studies show that antimicrobial peptides produced by gastropods such as marine snail Charonia tritonis, such as Ct-20534 and Ct-Mpeg1, and Ct-PGRP-S1, exhibit moderate antipathogenic effects towards major aquaculture pathogens, including Vibrio parahaemolyticus, Vibrio alginolyticus, and Vibrio cholerae (Wong et al., 2025). Also, such compounds as niuhinone A-C of Philinopsis speciosa and terpene derivatives of Doto pinnatida emphasize the structural diversity and untapped opportunities of gastropod-derived secondary metabolites as novel source of antibacterial agents (Shahidi and Santhiravel, 2022). These exudates are complex mixtures of glycoproteins, enzymes, and peptides, which mediate locomotion and defense, show a variety of biological activity in therapeutic applications, e.g., wound healing and antimicrobial therapy (Rashad et al., 2023). Outside of these, extensive gastropod-wide studies of gastropods such as Octopus vulgaris have found candidate proteins and peptides that have biotechnological uses in both gastropod skin mucus and ink, demonstrating the possibility of a new bioactive compound discovery (Cabral et al., 2024). Such investigations are critical given that a significant proportion of mollusk-derived secondary metabolites remain uncharacterized for their biological activities (Shahidi & Santhiravel, 2022). Table 10 Key gastropod-derived bioactive metabolites, their tissue sources, target pathogens or biological effects, and principal activities relevant to aquaculture health management.

Table 10. Key gastropod-derived metabolites from select species

Compound	Source	Gastropod species	Target pathogens/effects	Activity	Reference
Haliotisins	Hemocyanin	Haliotis tuberculata	Gram+/− bacteria	Membrane disruption, antibacterial	(Zhuang et al., 2014)
Bioactive peptides	Viscera	Haliotis fulgens, H. corrugata	Bacteria	Antimicrobial	(Rivera-Pérez et al., 2023)
Mucus glycoproteins	Skin mucus	Bolinus brandaris	Pathogens, cancer cells	Cytotoxic, immunomodulant	(Sansone et al., 2022)
Plasma proteins	Hemolymph	Gastropods (e.g., abalone)	Viruses	Antiviral	(Green et al., 2015; Watson et al., 2022)
Hemocyanin AMPs	Hemocytes	Haliotis spp.	Vibrio spp., viruses	Antimicrobial, antiviral	(Valtchev, 2018; Watson et al., 2022)

6.3         Mechanisms and Potential for Application in Mollusk and Finfish Farming

Mollusk-derived antimicrobial peptides and proteins primarily exert their effects through cationic amphipathic structures that facilitate membrane disruption, pore formation, and intracellular targeting in Gram-positive and Gram-negative bacteria, as well as viruses (Bachère et al., 2015; Hajigha et al., 2024; Schmitt et al., 2012). Big defensins from bivalves like Crassostrea gigas form nanonets via their N-terminal domain to entrap pathogens, preventing invasion, while defensins inhibit peptidoglycan synthesis and BPIs increase permeability (Bachère et al., 2015; Canesi et al., 2022; Ulagesan et al., 2022). Gastropod hemocyanin-derived haliotisins adopt α-helical conformations to permeabilize bacterial membranes (Zhuang et al., 2014), and multi-functional plasma proteins exhibit broad-spectrum antiviral activity, potentially via interferon-like responses and autophagy in bivalves (Green et al., 2015; Novoa et al., 2016; Watson et al., 2022). Sequence diversity enables synergies, as co-localized AMP families enhance efficacy against Vibrio spp.

Even though the concentrations are not high at the individual level (Nicolas et al., 2022; Schmitt et al., 2012). In addition to direct bactericidal activity, some mollusk-derived products, including the ones present in abalone, can have immunomodulatory properties and increase immunity of the host against pathogens (Valtchev, 2018). As an illustration, skin mucus of octopuses and other mollusks were demonstrated to have not only antimicrobial effect but also antioxidant activity, indicating a complex defensive use (Mathiessen et al., 2023; Perez-Polo et al., 2023). In addition, the synergy between the bioactive compounds present in these secretions can be useful in offering effective protection to environmental stressors and pathogenic intrusions (Cabral et al., 2024; Perez-Polo et al., 2023). This synergetic action highlights their possible potential as a source of new biomolecules with therapeutic uses in aquaculture (Diaz-Puertas et al., 2023; Perez-Polo et al., 2023; Tiralongo et al., 2020). But as Fig. 1 indicates, the processes and possibilities of use in mollusk and finfish farming are open. These compounds have tremendous potential as alternative antibiotics in aquaculture, although their saline stability in aquaculture is improved, which is applicable in both finfish and mollusk farming (Beltran et al., 2023; Rodrigues et al., 2025).

Fig. 1. shows the mechanisms and potential for application in mollusk and finfish farming.

Dietary supplementation of recombinant or hydrolyzed AMPs improves growth, immune responses, and vibriosis resistance in abalone (Haliotis discus hannai) (Chen et al., 2020), while omics studies confirm post-challenge upregulation of immune genes (Nguyen & Alfaro, 2019; Yang et al., 2021). In oysters and mussels, in vivo validation supports feed additive use for OsHV-1 and bacterial resistance (Destoumieux‐Garzón et al., 2020; Novoa et al., 2016). Cross-phyla applications to finfish target shared pathogens like V. parahaemolyticus, with potential via CRISPR transgenesis or therapeutics (Guryanova et al., 2023; Rodrigues et al., 2025; Tong et al., 2021). Challenges include scalability from variable tissues, stability, and comprehensive field trials, but standardization promises sustainable deployment (Naiel et al., 2023; Rodrigues et al., 2025).

7           Less Conventional Aquatic Sources

7.1         Echinoderms (e.g., Sea Cucumbers, Starfish)

Echinoderms, encompassing sea cucumbers, starfish, and sea urchins, yield diverse antimicrobial compounds including triterpene glycosides (saponins), cysteine-rich peptides, and lipid extracts primarily from coelomocytes, body walls, gonads, and viscera(Ghelani et al., 2022; Kalinin, 2021; Khotimchenko, 2018). These bioactive molecules from species like Echinus esculentus, Holothuria leucospilota, Linckia laevigata, and Diadema setosum exhibit broad-spectrum activity against Gram-positive/negative bacteria, fungi, and some viruses via membrane permeabilization and cytotoxicity (Darya et al., 2020; Obukhova et al., 2022; Solstad et al., 2016). Coelomic fluid-derived AMPs such as EeCentrocins 1/2 and EeStrongylocin 2 from sea urchins demonstrate potent low-μM inhibition of bacteria and fungi (Solstad, 2016; Solstad et al., 2016). Sea cucumber saponins and extracts show antifungal dominance alongside antibacterial effects (Khotimchenko, 2018).

Echinoderms, encompassing sea cucumbers, starfish, and sea urchins, yield diverse antimicrobial compounds including triterpene glycosides (saponins), cysteine-rich peptides, and lipid extracts primarily from coelomocytes, body walls, gonads, and viscera. These metabolites are summarized in Table 11 highlighting their tissue sources, primary targets, and principal bioactivities relevant to aquaculture.​

Despite challenges like saponin toxicity to non-target organisms, variable yields, and limited scalability compared to mollusks, fractionation, enzymatic hydrolysis, and recombinant strategies offer production feasibility for aquaculture(Guryanova et al., 2023; Rodrigues et al., 2025). Preliminary in vitro data support potential against shared aquaculture pathogens like Vibrio spp., with omics hinting at immune modulation(Guo & Li, 2020; Kawsar et al., 2025). Further in vivo trials in sea cucumber/urchin farming and cross-application to bivalves/finfish are warranted to harness their untapped antimicrobial potential(Sibiya et al., 2021; Wu et al., 2021). Indeed, studies compiling over 350 antimicrobial peptides from aquatic invertebrates, predominantly cationic and α-helical, highlight their suitability for high-salinity environments and their potential as feed additives or therapeutic agents through genetic engineering (Rodrigues et al., 2025).

These innate defense mechanisms are essential to echinoderms, which do not have an adaptive immune system, and use compounds such as complement factors, lectins, lysozymes, and antimicrobial peptides to cope with high bacterial loads in their habitats (Solstad et al., 2016). Furthermore, antimicrobial peptides in some echinoderms such as sea urchins and sea cucumbers have been shown to have a high antimicrobial activity against multidrug-resistant bacterial strains including biofilm-forming ones (Schillaci, 2014; Schillaci et al., 2013). Their wide-range activity, including antibacterial, antifungal, antiviral, and antiparasitic effects, is what makes them promising agents to overcome the increasing crisis of antimicrobial resistance in aquaculture (Kawsar et al., 2025). The utilization of echinoderm gut biomass as a co-product is also another way to increase sustainability, providing a source of bioactive compounds with antibacterial properties based on a by-product of gonad processing (Pagels et al., 2023). As an example, sea cucumber Holothuria leucospilota crude extracts have shown significant antibacterial effects against different Streptococcus species, and some extracts have both considerable antibacterial and hemolytic effects against bacterial growth, which is a key factor when considering pharmaceutical use (Ghadiri et al., 2018).

Table 11. Key echinoderm-derived bioactive metabolites, their tissue sources, target pathogens or biological effects, and principal activities relevant to aquaculture health management.

Compound	Source	Echinoderm species	Target pathogens/effects	Activity	Reference
Triterpene glycosides (saponins)	Body wall, gonads	Holothuria spp., Stichopus spp.	Bacteria, fungi	Membrane disruption, antifungal, antibacterial	(Khotimchenko, 2018)
EeCentrocin 1, 2	Coelomocytes/hemocytes	Echinus esculentus	Gram+/− bacteria, fungi	Antimicrobial	(Solstad et al., 2016)
EeStrongylocin 2	Coelomocytes/hemocytes	Echinus esculentus	Bacteria, fungi	Antimicrobial	(Solstad et al., 2016)
Lipid extracts	Liver, gonads	Linckia laevigata, Culcita novaeguineae, Diadema setosum	Gram+, Gram− bacteria, Candida	Antibacterial	(Obukhova et al., 2022)
Bioactive extracts	Body wall, gonads, cuvierian tubules	Holothuria leucospilota	Bacteria (antibacterial, antifouling)	Antibacterial	(Darya et al., 2020)
Novel peptides (e.g., from Patiria pectinifera)	Hemocytes	Patiria pectinifera	Bacteria	Antimicrobial	(Kim et al., 2018)

 

7.2         Cnidarians and Other Invertebrates

Cnidarians (jellyfish, sea anemones, corals, and hydroids) synthesize diverse antimicrobial substances, including cysteine-rich peptides (e.g., defensins), bioactive extracts, microbiome-derived agents, mainly tentacles, mucus, tissues, and related microbiota(Leal et al., 2022; Mariottini and Grice, 2016; Wu et al., 2021). These species-independent molecules such as Aurelia aurea, Phylogorgia dilatata, and sea anemones show activities against Gram-positive/negative bacteria, such as aquaculture pathogens such as Vibrio spp., through membrane disruption and cytotoxicity(Kawsar et al., 2025; Leon-Palmero et al., 2018; Ovchinnikova and Shi, 2023). Examples are aurelin, a defensin-like jellyfish coelenterocyte-derived peptide, which exhibits potent anti-Gram+/-bacteria(Ovchinnikova and Shi, 2023) and Pd-AMP1 of gorgonian corals, which has the strong anti-Staphylococcus aureus activity(Macedo et al., 2021). The cnidarian crude extracts have shown an inhibition rate of 33-94% against pathogens such as E. coli, S. aureus, and Salmonella typhimurium(Macedo et al., 2021). In spite of such obstacles as toxin co-occurrence, low productivity, climate-related environmental pressures, and poor structural characterizations relative to other phyla, recombinant expression, omics-based discovery, and fractionation improve the possibility of production in aquaculture(Guryanova et al., 2023; Ovchinnikova & Shi, 2023; Wu et al., 2021). Early evidence suggests that it is effective against common pathogens such as Vibrio in corals and fish, and may stimulate immune through innate mechanisms(Kawsar et al., 2025; Leon-Palmero et al., 2018; Rodrigues et al., 2025). More in vivo experiments in finfish/shrimp farming and cross-phylal applications are necessary, as well as experimentation with alternative invertebrates such as polychaetes (e.g., Hediste diversicolor) as complementary AMPs(Cabral et al., 2024; Wu et al., 2021). Research identifies approximately 350 aquatic invertebrate AMPs, such as Cnidaria AMPs, as being stable in saline environments to use as feed additives or CRISPR therapeutics (Rodrigues et al., 2025). Numerous of these antimicrobial peptides, especially the defensins of cnidarians, are multifaceted in their properties, which allow them to attack exogenous pathogens in different ways, such as disrupting the membrane and interfering with intracellular molecular targets (Ovchinnikova & Shi, 2023). In addition to antimicrobial peptides, cnidarians provide a variety of bioactive substances, such as antitumor peptides of sea anemones such as Anthopleura anjunae (Macedo et al., 2021). Table 12 emphasizes the bioactive metabolites of cnidarians, species exemplar, key targets, and key functions.

Table 12. Key cnidarian-derived bioactive metabolites, their tissue sources, representative cnidarian species, target pathogens or biological effects, and principal activities relevant to aquaculture health management.

Compound	Source	Cnidarian species	Target pathogens/effects	Activity	Reference
Aurelin	Coelenterocytes	Aurelia aurita (jellyfish)	Gram+/− bacteria	Antimicrobial	(Ovchinnikova & Shi, 2023)
Pd-AMP1	Crude extract	Phyllogorgia dilatata (gorgonian)	Staphylococcus aureus	Antibacterial	(Macedo et al., 2021)
Crude extracts	Tentacles/tissues	Carijoa riisei, Plexaurella grandiflora, etc.	S. aureus, E. coli, Salmonella spp., etc.	Antibacterial (33–94% inhibition)	(Macedo et al., 2021)
Microbiome metabolites	Associated microbiota	Sea anemones	Vibrio spp., other bacteria	Antimicrobial	(León‐Palmero et al., 2018)

8           Challenges, Limitations, and Future Perspectives

In summary, marine invertebrate-derived antimicrobial peptides have many practical and regulatory challenges but have potential future applications in sustainable aquaculture intervention. Diversity in species, geography, seasonality, and extraction conditions results in inconsistent crude extracts, frequently containing toxins or impurities, which complicates the standardization and reproducible potency, highlighting the necessity of sophisticated fractionation, omics profiling, and standardized protocols to ensure batch-to-batch consistency (Macedo et al., 2021; Wu et al., 2021; Guryanova et al., 2023; Cabral et al., 2024; Wu et al., Low natural yields, high purification costs and peptide instability further limit the scaling of production between the laboratory and industry, and therefore recombinant systems in bacteria, yeast, or plants and chemical synthesis are under investigation despite expression toxicity and folding problems, in regulatory frameworks that demand much safety data and are ill-adapted to immunomodulatory agents, slowing approvals of additives as feed additives or therapies (Sinha & Shukla, 2018; Wu et al., 2021; Macedo et al., 2021; Dijk et al., 2018).

Although AMPs generally exhibit low resistance induction potential due to multi-target mechanisms, prolonged or suboptimal exposure could still select resistant strains, while off-target effects such as hemolysis and cytotoxicity narrow the therapeutic window, particularly in saline conditions, and uncertainties about environmental persistence, degradation, and bioaccumulation demand ecotoxicological assessments to safeguard non-target aquatic organisms (Naiel et al., 2023; Rodrigues et al., 2025; Naiel et al., 2023; Reverter et al., 2020; Yuan et al., 2023). At the same time, omics-driven discovery (genomics, transcriptomics, proteomics) and AI-enabled bioinformatics accelerate identification of novel AMPs from understudied taxa and support in silico design of analogs with improved stability, activity, and resistance-evasion profiles tailored to aquaculture pathogens, while biotechnological platforms using recombinant expression, fusion tags, and synthetic analogs help overcome natural limitations such as low yield and protease sensitivity, improving bioavailability for feed incorporation or therapeutic delivery (Cabral et al., 2024; Ovchinnikova & Shi, 2023; Barroso et al., 2025; Lou et al., 2025; Macedo et al., 2021; Sinha & Shukla, 2018; Wang et al., 2023; Wu et al., 2021). Looking ahead, key research priorities to mitigate antimicrobial resistance in aquaculture include robust in vivo trials in finfish and shrimp, evaluation of cross-phyla efficacy against Vibrio and multidrug-resistant strains, integration of CRISPR strategies to enhance host AMP production, long-term field validations coupled with resistance surveillance, and sustainable sourcing via mariculture, all of which are essential to bridge the gap between experimental promise and practical, responsible deployment (Naiel et al., 2023; Rodrigues et al., 2025; Beltrán et al., 2023; Wu et al., 2021).

9           Conclusion 

In conclusion, existing results suggest that aquatic animals, especially marine invertebrate species of phyla such as Cnidaria, are a prolific source of antimicrobial peptides and bioactive metabolites with the ability to act on a broad spectrum against aquaculture pathogenic microorganisms like Vibrio spp., Staphylococcus aureus, Escherichia coli, and Salmonella with approximately 350 known examples of cnidarian-derived AMP acting via membrane disruption, intracell These compounds have significant potential as sustainable aquaculture by suppressing antibiotic use in finfish and shrimp farming through salinity-tolerant, low-resistance multi-target alternatives to antibiotics with enhancement of innate immunity, the provision of ancillary antitumor and immunomodulatory activity, and may be used as a feed additive, therapeutic, or CRISPR-enhanced transgenic to minimize mortality and antibiotic use as well as to limit environmental residues and AMR selection pressure. To achieve this potential, it will require addressing long-standing issues of low natural yields, variability and standardization of extracts, production cost, and strict regulatory frameworks through omics-assisted discovery, recombinant and synthetic production systems, and AI-assisted peptide design, accompanied by increased in vivo efficacy and safety studies, resistance surveillance, cultured-based mariculture sourcing, and policy changes that explicitly embrace immunomodulators, and facilitating the adoption of AMPs into commercial aquaculture and helping the world switch to antibiotic-free production systems.

Funding: No funding available for this study.

Authors Contribution: All authors contributed equally to this work.

Ethical approval: Not applicable

Informed consent: Not applicable.

Conflicts of interest: There is no conflict of interest to declare.

Data availability statement: Not applicable.

Declaration of using AI Technology: The author(s) declared that they did not use generative AI and AI assisted technologies in the writing process.

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