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Review

Marine Antimicrobial Peptides: Emerging Strategies Against Multidrug-Resistant and Biofilm-Forming Bacteria

by
Rita Magalhães
1,*,
Dalila Mil-Homens
2,
Sónia Cruz
1 and
Manuela Oliveira
3,4,5,*
1
ECOMARE—Laboratory for Innovation and Sustainability of Marine Biological Resources, CESAM—Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
2
ITQB NOVA—Instituto de Tecnologia Química e Biológica António Xavier, NOVA University of Lisbon, Av. da República, 2780-157 Oeiras, Portugal
3
CIISA—Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade Técnica, 1300-477 Lisbon, Portugal
4
AL4AnimalS—Associate Laboratory for Animal and Veterinary Sciences, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade Técnica, 1300-477 Lisbon, Portugal
5
cE3c—Centre for Ecology, Evolution and Environmental Changes, CHANGE—Global Change and Sustainability Institute, Faculty of Sciences, University of Lisbon, Campo Grande, 1749-016 Lisbon, Portugal
*
Authors to whom correspondence should be addressed.
Antibiotics 2025, 14(8), 808; https://doi.org/10.3390/antibiotics14080808
Submission received: 30 June 2025 / Revised: 28 July 2025 / Accepted: 4 August 2025 / Published: 7 August 2025
(This article belongs to the Section Antimicrobial Peptides)
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Abstract

The global rise in antimicrobial resistance poses a major threat to public health, with multidrug-resistant bacterial infections expected to surpass cancer in mortality by 2050. As traditional antibiotic pipelines stagnate, novel therapeutic alternatives are critically needed. Antimicrobial peptides (AMPs), particularly those derived from marine organisms, have emerged as promising antimicrobial candidates due to their broad-spectrum activity, structural diversity, and distinctive mechanisms of action. Unlike conventional antibiotics, AMPs can disrupt microbial membranes, inhibit biofilm formation, and even modulate immune responses, making them highly effective against resistant bacteria. This review highlights the potential of marine AMPs as next-generation therapeutics, emphasizing their efficacy against multidrug-resistant pathogens and biofilm-associated infections. Furthermore, marine AMPs show promise in combating persister cells and disrupting quorum sensing pathways, offering new strategies for tackling chronic infections. Despite their potential, challenges such as production scalability and limited clinical validation remain; nevertheless, the use of new technologies and bioinformatic tools is accelerating the discovery and optimization of these peptides, paving the way for bypassing these challenges. This review consolidates current findings on marine AMPs, advocating for their continued exploration as viable tools in the fight against antimicrobial resistance.

1. Introduction

In recent decades, the world has faced a growing crisis due to antimicrobial resistance, with infections by resistant strains having directly and indirectly resulted in 4.71 million deaths in 2021 [1,2,3]. As this problem expands each year, mainly due to the overuse and misuse of antibiotics worldwide, infections caused by multidrug-resistant (MDR) bacteria are expected to become deadlier than cancer by 2050 [4]. Adding to the challenge, the development of new antibiotics has significantly slowed [5]. Therefore, it is mandatory to invest in the development of new drugs and alternatives for fighting resistant strains, to avoid the risk of returning to a pre-antibiotic era.
One alternative to conventional antibiotics that has attracted increasing attention from the scientific community for some years now is the use of antimicrobial peptides (AMPs) produced by plants and animals. AMPs are part of the innate immune system of all life forms and have shown a wide range of biological properties, such as antibacterial, antiviral, antiprotozoal, antifungal, anticancer, antioxidant, antihypertensive, antidiabetic, anticoagulant, anti-inflammatory, cardioprotective, neuroprotective and immunoregulatory effects [6,7,8]. As of December 2024, the Antimicrobial Peptide Database 3 (APD3) contains information on 5099 peptides, from which 3306 correspond to natural compounds produced by members of the six life kingdoms (Figure 1) [9,10,11,12,13,14,15]. This database includes 4648 entries corresponding to molecules with antibacterial potential, from which 172 show antibiofilm properties and 605 present activity against methicillin-resistant Staphylococcus aureus (MRSA) [10].
AMPs were first identified in the 1980s, with the first peptide from marine sources, tachyplesin, being described in 1988 [16]. Despite being discovered almost at the same time period, marine AMPs have received significantly less attention than their terrestrial counterparts, accounting for only ~4% of known AMPs in existing databases [17,18,19]. Seawater harbors greater biological and genetic diversity than any other environment, encompassing organisms from bacteria and small invertebrates to complex vertebrates, many of which exhibit unique adaptations to extreme conditions [17]. As such, it is expected that the number and diversity of bioactive molecules from marine organisms will also surpass those discovered in terrestrial lifeforms [19]. Despite this remarkable biodiversity, the exploration of the antibacterial potential of marine species continues to face numerous challenges, leaving much of its potential unexploited [17,20].
In recent years, the scientific community has developed and significantly improved Omics methodologies (genomics, transcriptomics, proteomics, metabolomics, and multiomics) and bioinformatic tools, which have played a pivotal role in the discovery of novel bioactive compounds, contributing significantly to the advancement of the field. These approaches enable high-throughput screening of marine genomes and transcriptomes, accelerating the discovery of peptides with antimicrobial potential [5,17].
In this review, marine AMPs are presented as alternatives to both conventional antibiotics and terrestrial AMPs in the fight against pathogenic MDR bacteria, including biofilm-forming strains. We first describe the general structural and functional characteristics of antimicrobial peptides, with an emphasis on marine-derived AMPs. We then explore their activity against multidrug-resistant bacteria, including their ability to inhibit biofilm formation and target persister cells. Finally, we discuss current limitations in AMP development and propose future directions for their clinical application. While the biological and antimicrobial properties of marine AMPs have been addressed in previous reviews, this work focuses on their antibacterial efficacy against both resistant and tolerant phenotypes.

2. Antimicrobial Peptides

AMPs are peptides with approximately 2 to 60 amino acids, and although some anionic AMPs have been described, generally they are positively charged, with +2 to +9 net charge. These molecules are expressed as part of the innate immune system of many organisms, being produced without eliciting harmful effects on the host organism [21,22]. Structurally, they are amphipathic, which enables them to easily attach to the membranes of the target pathogens, are cysteine-rich and present multiple intramolecular disulfide bridges [5,9,21,23,24]. Due to their broader range of biological effects in comparison with conventional antibiotics, AMPs are promising candidates for pharmacological applications [23]. Their wide spectrum of action, but also their toxicity, can be related to their structural diversity, which ranges from alpha helix to beta stand conformations [25,26,27].
AMPs are usually classified into five families according to their structure: linear α-helix peptides, β-sheet peptides, peptides with both an α-helix and β-sheet, peptides without an α-helix or β-sheet and topologically complex AMPs [28]. On another end, and even though AMPs present a great diversity of antimicrobial approaches, these peptides can be classified into two main categories according to their action mechanism: membrane-acting and non-membrane-acting [24]. In Figure 2, we represent the three main modes of action for membrane-acting peptides, namely the toroidal, barrel-stave and carpet-like models [24]. Their cationic nature is essential for the membrane-targeting mechanism, as it facilitates binding to the negatively charged phospholipidic membranes of pathogens. This, together with their ability to acquire amphipathic conformations, prompts the formation of pores in the microbial membranes, disrupting their integrity and promoting intracellular ion and metabolite leakage, which can culminate in cell death [26,29,30,31,32] (Figure 2).
AMPs exploit the differences between bacterial and eukaryotic membranes, which results in target selectivity. When targeting the membrane, AMPs link with the bilayer through their α-helix domains, while the β-folded domains are responsible for molecule stability and membrane crossing [33]. Besides acting at the membrane level, AMPs can also inhibit protein synthesis, negatively affect essential cellular processes and act as signalling molecules, modulating the host immune response [6,17]. Moreover, as they mainly act at the membrane level, their action mechanism limits the development of resistance, as this would require fundamental alterations of the bacterial membrane [34]. The reduced capacity of bacteria for developing resistance to AMPs, allied to their broad spectrum of activity, make these peptides perfect candidates for novel drug discovery [26].

3. Marine AMPs Against Antibiotic Resistance

Among the several sources of AMPs, marine species produce compounds with distinct biochemical properties and high therapeutic potential. Generally, marine creatures lack a developed acquired immune system, relying instead on innate immunity and defence strategies, in which AMPs are crucial [19,21,35]. When pathogen-associated molecular patterns (PAMPs) are detected in the surface of innate immunity receptors, signalling pathways are triggered, and phagocytosis and the production of antimicrobial substances are activated [36]. Most marine AMPs tolerate high salinity, pressure, and drastic fluctuations in pH, nutrient availability, oxygen levels and temperature, reflecting the highly competitive and demanding nature of their environment, contrary to their terrestrial and freshwater counterparts [1,12,34,37,38]. Likewise, organisms from the deep sea produce AMPs that are potentially better adapted to high-pressure environments, while AMPs from intertidal species tend to exhibit higher salt tolerance and resistance to desiccation [39]. In addition, marine AMPs usually present low cytotoxicity, high bioavailability and no haemolytic properties, although more in vivo studies are needed to confirm these traits [12,40]. These characteristics, combined with their high stability, support the previously proposed hypothesis that marine AMPs are ideal candidates for the development of next-generation antimicrobials.
Antimicrobial resistance can be inherent (intrinsic), acquired or a combination of both. Intrinsic antimicrobial resistance is a natural, universal trait of a bacterial species, making it innately non-susceptible to certain antibiotics, even without prior exposure to antimicrobials or the acquisition of resistance genes. Acquired resistance arises when previously susceptible bacteria develop resistance through genetic mutations or by acquiring resistance genes via horizontal gene transfer from other organisms. Resistance can occur through the production of antibiotic-inactivating enzymes, the modification of drug target sites, alterations in cell wall or outer membrane permeability, and the activation of antibiotic efflux pumps [4,41]. Many nosocomial infections are nowadays related to highly resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Extended-spectrum beta-lactamase (ESBL) producing Gram-negative bacteria, resistant to all β-lactam antibiotics. The marine-derived AMPs that have demonstrated activity against multidrug-resistant bacteria are presented in Table 1.

4. Marine AMPs Against Biofilm

Beyond their activity against planktonic bacterial cells, marine AMPs have also shown significant potential in disrupting biofilms, the key bacterial structures responsible for chronic infections and consequently for increasing patients’ morbidity and mortality [62]. Biofilms are structured communities of microorganisms encased in a self-produced extracellular polymeric matrix, which attach to both living and non-living surfaces, such as medical devices, tissues, and industrial equipment. Biofilms can be composed of single or multiple microbial species, including bacteria and fungi, and are recognized for their ability to withstand external stressors—such as changes in temperature, pH, nutrient availability, and exposure to antimicrobial agents—far more effectively than their free-floating (planktonic) counterparts. This resilience is responsible for the persistence and chronicity of biofilm-associated infections, which account for 65 to 80% of human infections, especially those related to implanted devices and chronic wounds [63,64].
Biofilm communities confer several advantages to microorganisms, namely enhanced survival, metabolic adaptability, and protection from the action of both antibiotics and host immune responses [65,66,67,68]. In fact, bacteria within biofilms can exhibit antibiotic resistance levels exceeding 1000-fold compared to planktonic cells, largely due to the physical barrier of the extracellular matrix and the presence of metabolically dormant “persister” cells that evade conventional therapies without undergoing genetic changes. This makes the treatment of biofilm-related infections particularly challenging, especially of those associated with multidrug-resistant (MDR) pathogens such as S. aureus, Pseudomonas aeruginosa, and Candida albicans [69].
Given these challenges, there is a growing interest in alternative strategies able to disrupt biofilms, with AMPs from marine sources emerging as promising candidates. AMPs are multifaceted: they can rapidly kill cells at the early stages of biofilm formation, interfere with the extracellular matrix to hinder cell propagation, disrupt bacterial communication and quorum sensing (QS) systems, and can act synergistically with other antimicrobial drugs to enhance efficacy and reduce the risk of resistance development [24] (Table 2).
A particularly innovative approach to disrupting these bacterial communities involves targeting the QS systems that regulate biofilm formation and bacterial virulence. Quorum sensing inhibitors (QSIs) derived from marine microbes, such as cyclodipeptide diketopiperazines (DKPs), have been shown to impede QS-regulated pathogenicity, including biofilm development and the production of virulence factors. For example, cyclo (l-Trp-l-Ser) from the marine bacterium Rheinheimera aquimaris and cyclo (l-Tyr-l-Pro) from the fungus Penicillium chrysogenum were found to significantly inhibit biofilm formation and reduce virulence factor production by P. aeruginosa, a notorious biofilm-forming and MDR pathogen. Another marine-derived molecule, nesfactin, is able to inhibit biofilm formation by multidrug-resistant P. aeruginosa by 90% without affecting cell growth, being also able to degrade key QS signalling molecules [64,70,71].
Pleurocidin is a 25 amino-acid-long AMP derived from the winter flounder (Pleuronectes americanus), first described in 1997 [72]. Besides its antimicrobial activity against Gram-positive and Gram-negative bacteria, pleurocidin exhibits activity against drug-resistant S. aureus and can inhibit biofilm at 2 times its MIC (minimum inhibitory concentration). When compared with oxacillin and clindamycin, this AMP presented better results when eradicating bacterial biofilms at low concentrations [42]. A study investigating pleurocidin as a potential therapeutic for dental caries found out that, at a concentration of 64 µg/mL, this molecule is capable of reducing the Streptococcus mutans biofilm often associated with this condition by 75.2%, revealing its potential for use in formulations such as chewing gum or mouthwash [73].
An AMP named Tachyplesin III, consisting of 17 amino acids, is extracted from Southeast Asian horseshoe crabs and presents antibacterial, antifungal and antiviral activity. It has also been shown that ureteral stents impregnated with tachyplesin III can affect P. aeruginosa ATCC 27853 biofilms. When combined with the intraperitoneal administration of piperacillin and tazobactam, this treatment reduced bacterial counts to one quarter of the levels observed with either treatment alone in vivo [74].
Gaduscidin-1, an AMP derived from Atlantic cod (Gadus morhua), has emerged as a promising candidate for combating bacterial biofilm formation under cystic fibrosis conditions in vitro. When used in combination with conventional antibiotics, namely kanamycin and ciprofloxacin, Gad-1 enhanced their antibacterial efficacy. However, the cytotoxicity associated with Gad-1 is still a major challenge. To address this, researchers are currently developing a nanocapsule-based delivery system to mitigate Gad-1’s toxic effects and improve its therapeutic potential [75].
Reptiles have also been shown to produce AMPs with antibiofilm properties, as reported by Ouyang et al. in 2022 [76]. Cm-CATH2 from Chelonia mydas and Hc-CATH from Hydrophis cyanocintus revealed the ability to inhibit Vibrio vulnificus and S. aureus biofilms. Besides their permeabilization effect on the cytoplasmic membrane, these molecules were also able to modulate the immune response, inhibiting the expression of induced pro-inflammatory cytokines by bacteria while stimulating the phagocytic innate response of largemouth bass [76]. These AMPs possess strong activity against pathogenic bacteria in vivo, the ability to inhibit biofilm formation and a low propensity to induce resistance, while having multiple immunomodulatory effects [76,77,78].
In echinoderms, two AMPs from the sea-cucumber Holothuria tubulosa and one from the sea-urchin Paracentrotus lividus have been shown to inhibit biofilm formation by S. aureus, S. epidermidis and P. aeruginosa. These peptides only present modest activity against planktonic cells; however, their ability to inhibit biofilm formation is high, probably due to their specific mechanism of action [79,80]. AMPs produced by molluscs have also been shown to present antibiofilm properties [81,82].
Despite the extensive investigation of their antimicrobial properties, the antibiofilm potential of AMPs remains largely underexplored, which represents a promising opportunity for the future discovery of effective antimicrobial compounds. A list of natural-occurring AMPs from marine sources with antibiofilm activity can be found in Table 1.
It is important to note that, despite the advances in AMP research, no antibiofilm molecules have yet been approved for clinical use, so the discovery of new agents produced by marine microbial sources remains an active and promising area of research. The structural diversity and unique mechanisms of action of marine peptides offer significant potential for the development of novel therapeutic approaches capable of overcoming the defence mechanisms of biofilm-associated pathogens. As research continues, the integration of synthetic biology approaches may further enhance the efficacy and spectrum of these natural products, paving the way for the more effective management of biofilm-related infections [64].
Besides biofilms, persister cells also exhibit high tolerance to environmental stressors and resistance to antibiotic treatment, because these mainly target growth mechanisms and factors, which are inactive in persister cells. These cells are regulated by toxin–antitoxin systems, by alternative energy production mechanisms, by the SOS response to DNA damage, and by stringent responses, and can return to a normal growth rate once environmental conditions are ideal. Therefore, persistence is considered as adaptative resistance, which is associated with phenotypic variation [83,84,85,86]. Strategies to eradicate persister cells include the following: (a) the direct killing of the cells, even in their dormant state; (b) induction of resuscitation followed by conventional antibiotic therapy; (c) disruption of molecular pathways involved in persister cell formation to prevent their induction [87,88]. AMPs have been explored as a promising strategy to eliminate persister cells. Even though persisters can survive under stressful conditions, they still need an intact membrane to remain viable. Therefore, their ability to perturb the bacterial membrane make AMPs ideal candidates for the fight against persisters [89]. In the marine realm, Piscidine 3, an AMP from the hybrid striped seabass, was found to be effective against persisters due to its strong nuclease activity [90].
Table 2. List of AMPs from marine sources with antibiofilm properties. Abbreviations: MBIC, minimum biofilm inhibitory concentration; MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration; ROS, reactive oxygen species; QS, quorum sensing.
Table 2. List of AMPs from marine sources with antibiofilm properties. Abbreviations: MBIC, minimum biofilm inhibitory concentration; MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration; ROS, reactive oxygen species; QS, quorum sensing.
CompoundSourceMechanism of ActionAntibiofilm ActivityReferences
PleurocidinWinter flounder (Pleuronectes americanus)Membrane permeation and metabolic inhibitionS treptococcus mutans (75% reduction at 64 µg/mL); S. aureus (MBIC of 4 µM)[42,45,73]
Tachyplesin IIIHorseshoe crabs (Tachypleus gigas and Carcinoscorpius rotundicauda)Disruption of the cell membrane structure and ROS productionPseudomonas aeruginosa ATCC 27853 (MIC and MBC values of 4 and 32 µg/mL alone and 2 µg/mL and 8 µg/mL when associated with piperacillin-tazobactam)[74,91]
Gaduscidin-1Atlantic codfish (Gadus morhua)Reducing biofilm adhesion and ROS productionP. aeruginosa PAO1 biofilms show less 15 to 27% adhesion values (0.5 μM)[75]
Cm-CATH2Green sea turtle (Chlonia mydas)Membrane permeation and cell disruptionVibrio vulnificus (73.68% reduction), Staphylococcus aureus CMCC26003 (77.77% reduction), Enterococcus faecium (93% reduction) and S. aureus (96% reduction)[76,77]
Hc-CATHSea snake (Hydrophis
cyanocinctus)		Membrane permeation and cell disruptionV. vulnificus (74.55% reduction) and S. aureus CMCC26003 (71.64% reduction)[76]
Holothuroidin 1Sea-cucumber (Holothuria tubulosa)Interference with the initial bacterial adhesion, elimination of early bacterial colonizers and inhibition of QSS. aureus ATCC 25923 (51.8% reduction at 3.2 3200 mg/mL; 37.9% reduction at 1500 3.2 mg/mL), Staphylococcus epidermidis ATCC 35984 (68.5% reduction at 3200 3.2 mg/mL; 58.2% reduction at 1500 3.2 mg/mL) and P. aeruginosa ATCC 15442 (69.9% reduction at 6200 3.2 mg/mL; 62.7% reduction at 3100 3.2 mg/mL)[19,80]
Holothuroidin 2Sea-cucumber (Holothuria tubulosa)Interference with the initial bacterial adhesion, elimination of early bacterial colonizers and inhibition of QSS. aureus ATCC 25923 (57.7% reduction at 3200 μg/mL; 40.5% reduction at 1500 μg/mL), S. epidermidis ATCC 35984 (73.8% reduction at 3200 μg/mL; 59.7% reduction at 1500 μg/mL) and P. aeruginosa ATCC 15442 (64.3% reduction at 6200 μg/mL; 43.8% reduction at 3100 μg/mL)[19,80]
Paracentrin 1Sea-urchin (Paracentrotus lividus)UnknownS. aureus 25923, S. aureus 29213, S. aureus 6538, S. epidermidis RP62A and P. aeruginosa 15442 (~80% at 6200 μg/mL)[12,19,79]
Rpdef1αManila clam (Ruditapes
philippinarum)		Reduction in the initial attachment or stimulation of bacteria motility Escherichia coli MG1655 [82]
PhibilinTwo-striped slug Philomycus bilineatusPrevention of the development of hyphae by destruction of the budding sitesAction against biofilm formation but also mature Candida albicans biofilms [81]
CapitellacinPolychaeta (Capitella teleta)Membrane accumulation and consequent conductivity fluctuations. Membrane destruction when the threshold is reachedAction against biofilm formation but also E scherichia coli SBS 1936 mature biofilms [92]
LFX01Lactiplantibacillus plantarum strain LF-8UnknownShigella flexneri 14[93]
PontifactinPontibacter korlensis SBK-47Inhibition of microbial adhesionBacillus subtilis MRCC 619, S. aureus MTCC 96 and Vibrio cholerae MTCC3906 (99% reduction at 2000 μg/mL)[94]
Pumilacidin-like
cyclopeptide		Bacillus sp. 176Inhibition of microbial motility and adhesionP. aeruginosa and B. subtilis (>50% reduction at 300 μg/mL)[95]
Cyclo (Trp-Ser)Rheinheimera aquimaris QS102Inhibition of QS P. aeruginosa PAO1 (59.9% reduction at 200 μg/mL)[70]
Cyclo (L-Trp-L-Pro)Penicillium chruso genum DXY-1Inhibition of QS P. aeruginosa PAO1 (48% reduction at 500 μg/mL)[71]
NesfactinNesterenkonia sp. MSA31Inhibition of QS P. aeruginosa FSPA09 (90% reduction at 75,000 μg/mL)[96]
EpicotripeptinEpicoccum nigrum M13UnknownB. subtilis ATCC6633, S. aureus NRRLB-767 (100 µg/mL)[97]
Crustin (Pp-Cru)Blue swimmer crab (Portunus pelagicus)Membrane permeation and cell disruptionS. aureus, E. faecalis, P. aeruginosa, E. coli (100 μg/mL)[98]
Crustin (Ps-cr)Green tiger shrimp (Peaneaus semisulcatus)Inhibition of bacterial adherence Bacillus thuringiensis, B. pumilis, V. parahaemolyticus, and V. alginolyticuls (40 μg/mL)[99]

5. Current Challenges

Marine-derived AMPs have emerged as promising candidates due to their broad-spectrum activity and unique mechanisms of action, which make resistance development less likely. However, before AMPs can be considered a definitive solution to antimicrobial resistance, several challenges remain. Despite the plethora of information on their in vitro activities, significant gaps persist regarding their clinical applicability. Only a limited number of natural AMPs have even advanced to clinical trials, with the majority of research still confined to the preclinical stage [15,41]. Although the mechanisms of action of many marine AMPs have been partially elucidated, significant knowledge gaps remain, particularly regarding their pharmacokinetic profiles. In vivo, these peptides often present limited stability due to rapid enzymatic degradation and poor bioavailability caused by low permeability of nonbacterial membranes and rapid clearance from systemic circulation [100,101]. Moreover, in many cases, conventional antibiotics still show more efficacy than AMP applied alone. To enhance AMPs’ bioavailability and avoid these issues, some strategies are already in development (Table 3).
Finally, several challenges remain, including high production costs and technical limitations [110,111]. Chemical synthesis, while precise, is often costly and inefficient for large-scale production. Natural extraction from marine organisms is limited by low yields and the need for sustainable aquaculture systems. Semi-synthetic strategies and peptide engineering hold promise to overcome these hurdles but require further optimization and validation for clinical use. Continued innovation in scalable, cost-effective, and biologically compatible production methods is essential to translate marine AMPs into viable therapeutic agents [12,100,112].

6. Conclusions

Marine antimicrobial peptides (AMPs) represent promising candidates for the development of novel therapeutics to address antimicrobial resistance. Their structural diversity and broad-spectrum activity, including efficacy against multidrug-resistant pathogens, biofilm structures, and persister cells, make them valuable alternatives to conventional antibiotics. This review consolidates current findings on the mechanisms of action of marine AMPs and highlights key examples with proven in vitro and in vivo effectiveness. Despite these advances, their clinical application remains limited due to several challenges. Emerging technologies and continued research in this field are essential to fully realize the therapeutic potential of marine AMPs.

7. Future Directions

As Thomas and Antony stated, ‘the distinctiveness of marine antimicrobial peptides lies in their broad spectrum activity, mechanism of action, less cytotoxicity, and high stability, which form the benchmark for developing a potential therapeutic’ [12]. Fortunately, most challenges previously mentioned are likely to be solved as our understanding of these compounds continues to advance [21].
Synthetic or analog versions of marine AMPs can be developed with improved properties using biotechnological approaches, such as genetic engineering and Omic technologies, in order to optimize the production of pharmaceuticals from these sources [101,112,113,114]. Advances in bioinformatics and machine learning now enable the prediction of AMPs structure, function, and antimicrobial spectrum, accelerating the screening process and reducing experimental costs. Moreover, synthetic biology and peptidomimetic design allow the modification of marine peptides, improving stability, selectivity, and production scalability [100,101,114]. As these tools continue to evolve, they will be instrumental in addressing the current limitations related to marine AMPs, while also expanding the therapeutic pipeline of these compounds.
Marine-derived peptide drugs have made significant progress in pharmaceutical development, with notable examples such as ziconotide and brentuximab vedotin receiving FDA approval for clinical use [7,100]. The current global clinical pipeline includes 23 marine-derived compounds in various stages of clinical development, including plitidepsin (Aplidin®), PM00104, Kahalalide F, Hemiasterlin, Spisulosine, Pseudopterosin A, Salinosporamide A, Tetrodotoxin, Conotoxin G, Bryostatin 1, Demochlorella® and Plinabulin, reflecting the ongoing interest and investment in this field [115,116,117,118,119,120,121,122].
Notably, marine-derived pharmaceuticals include not only peptides and proteins but also other bioactive molecules with applications in oncology, and beyond [8]. In addition to their pharmaceutical uses, AMPs from marine sources are gaining attention as potential food preservatives due to their safety, digestibility, solubility, and effectiveness under acidic conditions, making them safer alternatives to conventional preservatives [8]. These advances emphasize the biotechnological and therapeutic potential of marine bioactive compounds, which span a diverse range of chemical structures and bioactivities. Given the rise in antimicrobial resistance genes and mechanisms, including biofilm formation and cellular dormancy, it is essential to continue exploring alternatives to conventional antibiotics and to further investigate the hidden arsenal of antimicrobial properties that these small peptides possess.

8. Materials and Methods

To explore the antibacterial potential of marine AMPs, approximately 150 articles were identified through searches on PubMed®. Keywords such as “marine”, “antimicrobial peptides”, “biofilm” and “antimicrobial resistance” were used. Articles written in English and published in peer-reviewed journals were included, without a restriction on the publication date, to ensure a comprehensive review. Studies were carefully screened for relevance to the topic. The Antimicrobial Peptide Database (APD3) was consulted to identify marine AMPs with antibiofilm and anti-MRSA properties. Graph generation was performed using Python (version 3.10).

Author Contributions

Conceptualization, R.M. and M.O.; methodology, R.M.; software, R.M.; validation, M.O., S.C. and D.M.-H.; formal analysis, R.M.; investigation, R.M.; resources, M.O., S.C. and D.M.-H.; data curation, R.M.; writing—original draft preparation, R.M.; writing—review and editing, R.M., M.O., S.C. and D.M.-H.; visualization, R.M.; supervision, M.O., S.C. and D.M.-H.; project administration, S.C.; funding acquisition, M.O., S.C. and D.M.-H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Portuguese Foundation for Science and Technology (FCT) under the fellowship 2024.05947.BD to R.M., grant 2020.03278.CEECIND to S.C. (https://doi.org/10.54499/2020.03278.CEECIND/CP1589/CT0012), and under CESAM project/grant UID/50006 + LA/P/0094/2020 (doi.org/10.54499/LA/P/0094/2020). S.C. acknowledges further support by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program, grant agreement no. 949880 (https://doi.org/10.3030/949880).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding authors upon reasonable request.

Acknowledgments

Graph generation was performed using Python (version 3.10) in Google Collaboratory. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AMPAntimicrobial Peptide
MDRMultidrug Resistant
APD3Antimicrobial Peptide Database 3
MRSAMethicillin-resistant Staphylococcus aureus
MICMinimal Inhibitory Concentration
MBICMinimum Biofilm Inhibitory Concentration
ROSReactive Oxygen Species
VREVancomycin-Resistant Enterococci
ESBLExtended-Spectrum Beta-Lactamase
QSQuorum Sensing
PAMPsPathogen-associated molecular patterns
QSIQuorum sensing inhibitors
DKPDiketopiperazine

References

  1. Ho, C.S.; Wong, C.T.H.; Aung, T.T.; Lakshminarayanan, R.; Mehta, J.S.; Rauz, S.; McNally, A.; Kintses, B.; Peacock, S.J.; de la Fuente-Nunez, C.; et al. Antimicrobial Resistance: A Concise Update. Lancet Microbe 2025, 6, 100947. [Google Scholar] [CrossRef]
  2. Murray, C.J.L.; Ikuta, K.S.; Sharara, F.; Swetschinski, L.; Robles Aguilar, G.; Gray, A.; Han, C.; Bisignano, C.; Rao, P.; Wool, E.; et al. Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis. Lancet 2022, 399, 629–655. [Google Scholar] [CrossRef]
  3. World Health Organization. Seventy-Eighth World Health Assembly-Daily Update: 27 May 2025. Available online: https://www.who.int/news/item/27-05-2025-seventy-eighth-world-health-assembly---daily-update--27-may-2025 (accessed on 27 July 2025).
  4. Xuan, J.; Feng, W.; Wang, J.; Wang, R.; Zhang, B.; Bo, L.; Chen, Z.-S.; Yang, H.; Sun, L. Antimicrobial Peptides for Combating Drug-Resistant Bacterial Infections. Drug Resist. Updat. 2023, 68, 100954. [Google Scholar] [CrossRef]
  5. Díaz-Puertas, R.; Adamek, M.; Mallavia, R.; Falco, A. Fish Skin Mucus Extracts: An Underexplored Source of Antimicrobial Agents. Mar. Drugs 2023, 21, 350. [Google Scholar] [CrossRef]
  6. Shahidi, F.; Saeid, A. Bioactivity of Marine-Derived Peptides and Proteins: A Review. Mar. Drugs 2025, 23, 157. [Google Scholar] [CrossRef]
  7. Santhiravel, S.; Dave, D.; Shahidi, F. Bioactives from Marine Resources as Natural Health Products: A Review. Pharmacol. Rev. 2025, 77, 100009. [Google Scholar] [CrossRef]
  8. Shahidi, F.; Santhiravel, S. Novel Marine Bioactives: Application in Functional Foods, Nutraceuticals, and Pharmaceuticals. J. Food Bioact. 2022, 19, 4–96. [Google Scholar] [CrossRef]
  9. Saucedo-Vázquez, J.P.; Gushque, F.; Vispo, N.S.; Rodriguez, J.; Gudiño-Gomezjurado, M.E.; Albericio, F.; Tellkamp, M.P.; Alexis, F. Marine Arthropods as a Source of Antimicrobial Peptides. Mar. Drugs 2022, 20, 501. [Google Scholar] [CrossRef]
  10. Wang, G.; Li, X.; Wang, Z. APD3: The Antimicrobial Peptide Database as a Tool for Research and Education. Nucleic Acids Res. 2016, 44, D1087–D1093. [Google Scholar] [CrossRef]
  11. Masso-Silva, J.; Diamond, G. Antimicrobial Peptides from Fish. Pharmaceuticals 2014, 7, 265–310. [Google Scholar] [CrossRef]
  12. Thomas, A.M.; Antony, S.P. Marine Antimicrobial Peptides: An Emerging Nightmare to the Life-Threatening Pathogens. Probiotics Antimicrob. Proteins 2024, 16, 552–578. [Google Scholar] [CrossRef]
  13. García, F.A.; Fuentes, T.F.; Alonso, I.P.; Bosch, R.A.; Brunetti, A.E.; Lopes, N.P. A Comprehensive Review of Patented Antimicrobial Peptides from Amphibian Anurans. J. Nat. Prod. 2024, 87, 600–616. [Google Scholar] [CrossRef]
  14. Van Hoek, M. Antimicrobial Peptides in Reptiles. Pharmaceuticals 2014, 7, 723–753. [Google Scholar] [CrossRef]
  15. Chen, P.; Ye, T.; Li, C.; Praveen, P.; Hu, Z.; Li, W.; Shang, C. Embracing the Era of Antimicrobial Peptides with Marine Organisms. Nat. Prod. Rep. 2024, 41, 331–346. [Google Scholar] [CrossRef]
  16. Lu, S.; Lin, J.; Jin, J.; Zhang, L.; Guan, Y.; Chen, H.; Wu, Y.; Zhang, W.; Luan, X. Tachyplesin I and Its Derivatives: A Pharmaco-Chemical Perspective on Their Antimicrobial and Antitumor Potential. Expert Opin. Drug Discov. 2022, 17, 1407–1423. [Google Scholar] [CrossRef]
  17. Kanaujia, K.A.; Wagh, S.; Pandey, G.; Phatale, V.; Khairnar, P.; Kolipaka, T.; Rajinikanth, P.S.; Saraf, S.A.; Srivastava, S.; Kumar, S. Harnessing Marine Antimicrobial Peptides for Novel Therapeutics: A Deep Dive into Ocean-Derived Bioactives. Int. J. Biol. Macromol. 2025, 307, 142158. [Google Scholar] [CrossRef]
  18. Sarkar, T.; Chetia, M.; Chatterjee, S. Antimicrobial Peptides and Proteins: From Nature’s Reservoir to the Laboratory and Beyond. Front. Chem. 2021, 9, 691532. [Google Scholar] [CrossRef]
  19. Guryanova, S.V.; Balandin, S.V.; Belogurova-Ovchinnikova, O.Y.; Ovchinnikova, T.V. Marine Invertebrate Antimicrobial Peptides and Their Potential as Novel Peptide Antibiotics. Mar. Drugs 2023, 21, 503. [Google Scholar] [CrossRef]
  20. Macedo, M.W.F.S.; Cunha, N.B.D.; Carneiro, J.A.; Costa, R.A.D.; Alencar, S.A.D.; Cardoso, M.H.; Franco, O.L.; Dias, S.C. Marine Organisms as a Rich Source of Biologically Active Peptides. Front. Mar. Sci. 2021, 8, 667764. [Google Scholar] [CrossRef]
  21. Wu, R.; Patocka, J.; Nepovimova, E.; Oleksak, P.; Valis, M.; Wu, W.; Kuca, K. Marine Invertebrate Peptides: Antimicrobial Peptides. Front. Microbiol. 2021, 12, 785085. [Google Scholar] [CrossRef]
  22. Yin, Z.-X.; He, W.; Chen, W.-J.; Yan, J.-H.; Yang, J.-N.; Chan, S.-M.; He, J.-G. Cloning, Expression and Antimicrobial Activity of an Antimicrobial Peptide, Epinecidin-1, from the Orange-Spotted Grouper, Epinephelus coioides. Aquaculture 2006, 253, 204–211. [Google Scholar] [CrossRef]
  23. Asensio-Calavia, P.; González-Acosta, S.; Otazo-Pérez, A.; López, M.R.; Morales-delaNuez, A.; Pérez De La Lastra, J.M. Teleost Piscidins—In Silico Perspective of Natural Peptide Antibiotics from Marine Sources. Antibiotics 2023, 12, 855. [Google Scholar] [CrossRef]
  24. Patra, A.; Das, J.; Agrawal, N.R.; Kushwaha, G.S.; Ghosh, M.; Son, Y.-O. Marine Antimicrobial Peptides-Based Strategies for Tackling Bacterial Biofilm and Biofouling Challenges. Molecules 2022, 27, 7546. [Google Scholar] [CrossRef]
  25. Hancock, R.E.W.; Sahl, H.-G. Antimicrobial and Host-Defense Peptides as New Anti-Infective Therapeutic Strategies. Nat. Biotechnol. 2006, 24, 1551–1557. [Google Scholar] [CrossRef]
  26. Semreen, M.H.; El-Gamal, M.I.; Abdin, S.; Alkhazraji, H.; Kamal, L.; Hammad, S.; El-Awady, F.; Waleed, D.; Kourbaj, L. Recent Updates of Marine Antimicrobial Peptides. Saudi Pharm. J. 2018, 26, 396–409. [Google Scholar] [CrossRef]
  27. Huang, Y.; Huang, J.; Chen, Y. Alpha-helical Cationic Antimicrobial Peptides: Relationships of Structure and Function. Protein Cell 2010, 1, 143–152. [Google Scholar] [CrossRef]
  28. Mura, M.; Wang, J.; Zhou, Y.; Pinna, M.; Zvelindovsky, A.V.; Dennison, S.R.; Phoenix, D.A. The Effect of Amidation on the Behaviour of Antimicrobial Peptides. Eur. Biophys. J. 2016, 45, 195–207. [Google Scholar] [CrossRef]
  29. Sengupta, D.; Leontiadou, H.; Mark, A.E.; Marrink, S.-J. Toroidal Pores Formed by Antimicrobial Peptides Show Significant Disorder. Biochim. Biophys. Acta (BBA)-Biomembr. 2008, 1778, 2308–2317. [Google Scholar] [CrossRef]
  30. Joo, H.-S.; Fu, C.-I.; Otto, M. Bacterial Strategies of Resistance to Antimicrobial Peptides. Philos. Trans. R. Soc. B Biol. Sci. 2016, 371, 20150292. [Google Scholar] [CrossRef]
  31. Sperstad, S.V.; Haug, T.; Blencke, H.-M.; Styrvold, O.B.; Li, C.; Stensvåg, K. Antimicrobial Peptides from Marine Invertebrates: Challenges and Perspectives in Marine Antimicrobial Peptide Discovery. Biotechnol. Adv. 2011, 29, 519–530. [Google Scholar] [CrossRef]
  32. Powers, J.-P.S.; Hancock, R.E.W. The Relationship between Peptide Structure and Antibacterial Activity. Peptides 2003, 24, 1681–1691. [Google Scholar] [CrossRef]
  33. Zhang, Y.; Bao, C.; Shen, L.; Tian, C.; Zang, X.; Chen, G.; Zhang, S. Microbial Cold Shock Proteins: Overview of Their Function and Mechanism of Action. Protein Pept. Lett. 2022, 29, 133–142. [Google Scholar] [CrossRef]
  34. Falanga, A.; Lombardi, L.; Franci, G.; Vitiello, M.; Iovene, M.; Morelli, G.; Galdiero, M.; Galdiero, S. Marine Antimicrobial Peptides: Nature Provides Templates for the Design of Novel Compounds against Pathogenic Bacteria. Int. J. Mol. Sci. 2016, 17, 785. [Google Scholar] [CrossRef]
  35. Lei, Y.; He, D.; Zhao, X.; Miao, L.; Cao, Z. Structure, Function, and Therapeutic Potential of Defensins from Marine Animals. Fish Shellfish Immunol. 2025, 163, 110365. [Google Scholar] [CrossRef]
  36. Inguglia, L.; Chiaramonte, M.; Arizza, V.; Turiák, L.; Vékey, K.; Drahos, L.; Pitonzo, R.; Avellone, G.; Di Stefano, V. Changes in the Proteome of Sea Urchin Paracentrotus Lividus Coelomocytes in Response to LPS Injection into the Body Cavity. PLoS ONE 2020, 15, e0228893. [Google Scholar] [CrossRef]
  37. Fraune, S.; Augustin, R.; Anton-Erxleben, F.; Wittlieb, J.; Gelhaus, C.; Klimovich, V.B.; Samoilovich, M.P.; Bosch, T.C.G. In an Early Branching Metazoan, Bacterial Colonization of the Embryo Is Controlled by Maternal Antimicrobial Peptides. Proc. Natl. Acad. Sci. USA 2010, 107, 18067–18072. [Google Scholar] [CrossRef]
  38. Khalifa, S.A.M.; Elias, N.; Farag, M.A.; Chen, L.; Saeed, A.; Hegazy, M.-E.F.; Moustafa, M.S.; Abd El-Wahed, A.; Al-Mousawi, S.M.; Musharraf, S.G.; et al. Marine Natural Products: A Source of Novel Anticancer Drugs. Mar. Drugs 2019, 17, 491. [Google Scholar] [CrossRef]
  39. Zhang, G.; Li, L.; Meng, J.; Qi, H.; Qu, T.; Xu, F.; Zhang, L. Molecular Basis for Adaptation of Oysters to Stressful Marine Intertidal Environments. Annu. Rev. Anim. Biosci. 2016, 4, 357–381. [Google Scholar] [CrossRef]
  40. Okeke, E.S.; Okagu, I.U.; Chukwudozie, K.; Ezike, T.C.; Ezeorba, T.P.C. Marine-Derived Bioactive Proteins and Peptides: A Review of Current Knowledge on Anticancer Potentials, Clinical Trials, and Future Prospects. Nat. Prod. Commun. 2024, 19, 1–19. [Google Scholar] [CrossRef]
  41. Barbosa, F.; Pinto, E.; Kijjoa, A.; Pinto, M.; Sousa, E. Targeting Antimicrobial Drug Resistance with Marine Natural Products. Int. J. Antimicrob. Agents 2020, 56, 106005. [Google Scholar] [CrossRef]
  42. Ko, S.J.; Kang, N.H.; Kim, M.K.; Park, J.; Park, E.; Park, G.H.; Kang, T.W.; Na, D.E.; Park, J.B.; Yi, Y.E.; et al. Antibacterial and Anti-Biofilm Activity, and Mechanism of Action of Pleurocidin against Drug Resistant Staphylococcus aureus. Microb. Pathog. 2019, 127, 70–78. [Google Scholar] [CrossRef]
  43. Hsu, H.-C.; Chen, M.-H.; Yeh, M.-L.; Chen, W.-J. Antibacterial and Anticancer Activities of Pleurocidin-Amide, a Potent Marine Antimicrobial Peptide Derived from Winter Flounder, Pleuronectes americanus. Mar. Drugs 2022, 20, 519. [Google Scholar] [CrossRef]
  44. Ramos, C.; Lorenz, K.; Putrinš, M.; Hind, C.K.; Meos, A.; Laidmäe, I.; Tenson, T.; Sutton, J.M.; Mason, A.J.; Kogermann, K. Fibrous Matrices Facilitate Pleurocidin Killing of Wound Associated Bacterial Pathogens. Eur. J. Pharm. Sci. 2024, 192, 106648. [Google Scholar] [CrossRef]
  45. McMillan, K.A.M.; Coombs, M.R.P. Investigating Potential Applications of the Fish Anti-Microbial Peptide Pleurocidin: A Systematic Review. Pharmaceuticals 2021, 14, 687. [Google Scholar] [CrossRef]
  46. Talandashti, R.; Mahdiuni, H.; Jafari, M.; Mehrnejad, F. Molecular Basis for Membrane Selectivity of Antimicrobial Peptide Pleurocidin in the Presence of Different Eukaryotic and Prokaryotic Model Membranes. J. Chem. Inf. Model. 2019, 59, 3262–3276. [Google Scholar] [CrossRef]
  47. Patrzykat, A.; Gallant, J.W.; Seo, J.-K.; Pytyck, J.; Douglas, S.E. Novel Antimicrobial Peptides Derived from Flatfish Genes. Antimicrob. Agents Chemother. 2003, 47, 2464–2470. [Google Scholar] [CrossRef]
  48. Juliano, S.A.; Serafim, L.F.; Duay, S.S.; Heredia Chavez, M.; Sharma, G.; Rooney, M.; Comert, F.; Pierce, S.; Radulescu, A.; Cotten, M.L.; et al. A Potent Host Defense Peptide Triggers DNA Damage and Is Active against Multidrug-Resistant Gram-Negative Pathogens. ACS Infect. Dis. 2020, 6, 1250–1263. [Google Scholar] [CrossRef]
  49. Miller, A.; Matera-Witkiewicz, A.; Mikołajczyk, A.; Wieczorek, R.; Rowińska-Żyrek, M. Chemical “Butterfly Effect” Explaining the Coordination Chemistry and Antimicrobial Properties of Clavanin Complexes. Inorg. Chem. 2021, 60, 12730–12734. [Google Scholar] [CrossRef]
  50. Naing, M.D.; Juliano, S.A.; Angeles-Boza, A.M. Synergy between the Clavanins as a Weapon against Multidrug-Resistant Enterobacter cloacae. RSC Med. Chem. 2024, 15, 2160–2164. [Google Scholar] [CrossRef]
  51. Juliano, S.A.; Pierce, S.; deMayo, J.A.; Balunas, M.J.; Angeles-Boza, A.M. Exploration of the Innate Immune System of Styela clava: Zn2+ Binding Enhances the Antimicrobial Activity of the Tunicate Peptide Clavanin A. Biochemistry 2017, 56, 1403–1414. [Google Scholar] [CrossRef]
  52. Duay, S.S.; Sharma, G.; Prabhakar, R.; Angeles-Boza, A.M.; May, E.R. Molecular Dynamics Investigation into the Effect of Zinc(II) on the Structure and Membrane Interactions of the Antimicrobial Peptide Clavanin A. J. Phys. Chem. B 2019, 123, 3163–3176. [Google Scholar] [CrossRef]
  53. Salimnejhad, Z.; Hassanzadazar, H.; Aminzare, M. Epinecidin-1 (an Active Marine Antimicrobial Peptide): Effects on the Survival of Inoculated Escherichia coli O157:H7 and Staphylococcus aureus Bacteria, Antioxidant, and Sensory Attributes in Raw Milk. Food Sci. Nutr. 2023, 11, 5573–5581. [Google Scholar] [CrossRef]
  54. Bolatchiev, A. Antimicrobial Peptides Epinecidin-1 and Beta-Defesin-3 Are Effective against a Broad Spectrum of Antibiotic-Resistant Bacterial Isolates and Increase Survival Rate in Experimental Sepsis. Antibiotics 2022, 11, 76. [Google Scholar] [CrossRef]
  55. Huang, H.-N.; Pan, C.-Y.; Su, B.-C.; Wu, H.-Y.; Chen, J.-Y. Epinecidin-1 Protects against Methicillin Resistant Staphylococcus aureus Infection and Sepsis in Pyemia Pigs. Mar. Drugs 2019, 17, 693. [Google Scholar] [CrossRef]
  56. Narayana, J.L.; Huang, H.-N.; Wu, C.-J.; Chen, J.-Y. Epinecidin-1 Antimicrobial Activity: In Vitro Membrane Lysis and In Vivo Efficacy against Helicobacter Pylori Infection in a Mouse Model. Biomaterials 2015, 61, 41–51. [Google Scholar] [CrossRef]
  57. Lee, S.-C.; Pan, C.-Y.; Chen, J.-Y. The Antimicrobial Peptide, Epinecidin-1, Mediates Secretion of Cytokines in the Immune Response to Bacterial Infection in Mice. Peptides 2012, 36, 100–108. [Google Scholar] [CrossRef]
  58. Pan, C.-Y.; Chen, J.-C.; Chen, T.-L.; Wu, J.-L.; Hui, C.-F.; Chen, J.-Y. Piscidin Is Highly Active against Carbapenem-Resistant Acinetobacter baumannii and NDM-1-Producing Klebsiella pneumonia in a Systemic Septicaemia Infection Mouse Model. Mar. Drugs 2015, 13, 2287–2305. [Google Scholar] [CrossRef]
  59. Huang, H.-N.; Chan, Y.-L.; Hui, C.-F.; Wu, J.-L.; Wu, C.-J.; Chen, J.-Y. Use of Tilapia Piscidin 3 (TP3) to Protect against MRSA Infection in Mice with Skin Injuries. Oncotarget 2015, 6, 12955–12969. [Google Scholar] [CrossRef]
  60. Peng, K.-C.; Lee, S.-H.; Hour, A.-L.; Pan, C.-Y.; Lee, L.-H.; Chen, J.-Y. Five Different Piscidins from Nile Tilapia, Oreochromis niloticus: Analysis of Their Expressions and Biological Functions. PLoS ONE 2012, 7, e50263. [Google Scholar] [CrossRef]
  61. Huang, H.-N.; Chan, Y.-L.; Wu, C.-J.; Chen, J.-Y. Tilapia Piscidin 4 (TP4) Stimulates Cell Proliferation and Wound Closure in MRSA-Infected Wounds in Mice. Mar. Drugs 2015, 13, 2813–2833. [Google Scholar] [CrossRef]
  62. Oliveira, M.; Cunha, E.; Tavares, L.; Serrano, I. P. aeruginosa Interactions with Other Microbes in Biofilms during Co-Infection. AIMS Microbiol. 2023, 9, 612–646. [Google Scholar] [CrossRef]
  63. Jamal, M.; Ahmad, W.; Andleeb, S.; Jalil, F.; Imran, M.; Nawaz, M.A.; Hussain, T.; Ali, M.; Rafiq, M.; Kamil, M.A. Bacterial Biofilm and Associated Infections. J. Chin. Med. Assoc. 2018, 81, 7–11. [Google Scholar] [CrossRef]
  64. Sukmarini, L.; Atikana, A.; Hertiani, T. Antibiofilm Activity of Marine Microbial Natural Products: Potential Peptide- and Polyketide-Derived Molecules from Marine Microbes toward Targeting Biofilm-Forming Pathogens. J. Nat. Med. 2024, 78, 1–20. [Google Scholar] [CrossRef]
  65. Ciofu, O.; Moser, C.; Jensen, P.Ø.; Høiby, N. Tolerance and Resistance of Microbial Biofilms. Nat. Rev. Microbiol. 2022, 20, 621–635. [Google Scholar] [CrossRef]
  66. Hall, C.W.; Mah, T.-F. Molecular Mechanisms of Biofilm-Based Antibiotic Resistance and Tolerance in Pathogenic Bacteria. FEMS Microbiol. Rev. 2017, 41, 276–301. [Google Scholar] [CrossRef]
  67. Stewart, P.S. Antimicrobial Tolerance in Biofilms. In Microbial Biofilms; Ghannoum, M., Parsek, M., Whiteley, M., Mukherjee, P.K., Eds.; ASM Press: Washington, DC, USA, 2015; pp. 269–285. ISBN 978-1-68367-091-9. [Google Scholar]
  68. Olsen, I. Biofilm-Specific Antibiotic Tolerance and Resistance. Eur. J. Clin. Microbiol. Infect. Dis. 2015, 34, 877–886. [Google Scholar] [CrossRef]
  69. Ciofu, O.; Rojo-Molinero, E.; Macià, M.D.; Oliver, A. Antibiotic Treatment of Biofilm Infections. APMIS 2017, 125, 304–319. [Google Scholar] [CrossRef]
  70. Sun, S.; Dai, X.; Sun, J.; Bu, X.; Weng, C.; Li, H.; Zhu, H. A Diketopiperazine Factor from Rheinheimera aquimaris QSI02 Exhibits Anti-Quorum Sensing Activity. Sci. Rep. 2016, 6, 39637. [Google Scholar] [CrossRef]
  71. Yu, X.; Li, L.; Sun, S.; Chang, A.; Dai, X.; Li, H.; Wang, Y.; Zhu, H. A Cyclic Dipeptide from Marine Fungus Penicillium chrysogenum DXY-1 Exhibits Anti-Quorum Sensing Activity. ACS Omega 2021, 6, 7693–7700. [Google Scholar] [CrossRef]
  72. Cole, A.M.; Weis, P.; Diamond, G. Isolation and Characterization of Pleurocidin, an Antimicrobial Peptide in the Skin Secretions of Winter Flounder. J. Biol. Chem. 1997, 272, 12008–12013. [Google Scholar] [CrossRef]
  73. Tao, R.; Tong, Z.; Lin, Y.; Xue, Y.; Wang, W.; Kuang, R.; Wang, P.; Tian, Y.; Ni, L. Antimicrobial and Antibiofilm Activity of Pleurocidin against Cariogenic Microorganisms. Peptides 2011, 32, 1748–1754. [Google Scholar] [CrossRef]
  74. Minardi, D.; Ghiselli, R.; Cirioni, O.; Giacometti, A.; Kamysz, W.; Orlando, F.; Silvestri, C.; Parri, G.; Kamysz, E.; Scalise, G.; et al. The Antimicrobial Peptide Tachyplesin III Coated Alone and in Combination with Intraperitoneal Piperacillin-Tazobactam Prevents Ureteral Stent Pseudomonas Infection in a Rat Subcutaneous Pouch Model. Peptides 2007, 28, 2293–2298. [Google Scholar] [CrossRef]
  75. Portelinha, J.; Angeles-Boza, A.M. The Antimicrobial Peptide Gad-1 Clears Pseudomonas aeruginosa Biofilms under Cystic Fibrosis Conditions. ChemBioChem 2021, 22, 1646–1655. [Google Scholar] [CrossRef]
  76. Ouyang, J.; Zhu, Y.; Hao, W.; Wang, X.; Yang, H.; Deng, X.; Feng, T.; Huang, Y.; Yu, H.; Wang, Y. Three Naturally Occurring Host Defense Peptides Protect Largemouth Bass (Micropterus salmoides) against Bacterial Infections. Aquaculture 2022, 546, 737383. [Google Scholar] [CrossRef]
  77. Qiao, X.; Yang, H.; Gao, J.; Zhang, F.; Chu, P.; Yang, Y.; Zhang, M.; Wang, Y.; Yu, H. Diversity, Immunoregulatory Action and Structure-Activity Relationship of Green Sea Turtle Cathelicidins. Dev. Comp. Immunol. 2019, 98, 189–204. [Google Scholar] [CrossRef]
  78. Carlile, S.R.; Shiels, J.; Kerrigan, L.; Delaney, R.; Megaw, J.; Gilmore, B.F.; Weldon, S.; Dalton, J.P.; Taggart, C.C. Sea Snake Cathelicidin (Hc-Cath) Exerts a Protective Effect in Mouse Models of Lung Inflammation and Infection. Sci. Rep. 2019, 9, 6071. [Google Scholar] [CrossRef]
  79. Schillaci, D.; Cusimano, M.G.; Spinello, A.; Barone, G.; Russo, D.; Vitale, M.; Parrinello, D.; Arizza, V. Paracentrin 1, a Synthetic Antimicrobial Peptide from the Sea-Urchin Paracentrotus lividus, Interferes with Staphylococcal and Pseudomonas aeruginosa Biofilm Formation. AMB Express 2014, 4, 78. [Google Scholar] [CrossRef]
  80. Schillaci, D.; Cusimano, M.; Cunsolo, V.; Saletti, R.; Russo, D.; Vazzana, M.; Vitale, M.; Arizza, V. Immune Mediators of Sea-Cucumber Holothuria tubulosa (Echinodermata) as Source of Novel Antimicrobial and Anti-Staphylococcal Biofilm Agents. AMB Express 2013, 3, 35. [Google Scholar] [CrossRef]
  81. Li, Z.; Jing, X.; Yuan, Y.; Shui, Y.; Li, S.; Zhao, Z.; Deng, B.; Zhang, W. In Vitro and In Vivo Activity of Phibilin Against Candida Albicans. Front. Microbiol. 2022, 13, 862834. [Google Scholar] [CrossRef]
  82. Lv, C.; Han, Y.; Yang, D.; Zhao, J.; Wang, C.; Mu, C. Antibacterial Activities and Mechanisms of Action of a Defensin from Manila Clam Ruditapes philippinarum. Fish Shellfish Immunol. 2020, 103, 266–276. [Google Scholar] [CrossRef]
  83. Van Den Bergh, B.; Fauvart, M.; Michiels, J. Formation, Physiology, Ecology, Evolution and Clinical Importance of Bacterial Persisters. FEMS Microbiol. Rev. 2017, 41, 219–251. [Google Scholar] [CrossRef]
  84. Yang, S.; Hay, I.D.; Cameron, D.R.; Speir, M.; Cui, B.; Su, F.; Peleg, A.Y.; Lithgow, T.; Deighton, M.A.; Qu, Y. Antibiotic Regimen Based on Population Analysis of Residing Persister Cells Eradicates Staphylococcus epidermidis Biofilms. Sci. Rep. 2015, 5, 18578. [Google Scholar] [CrossRef]
  85. Kester, J.C.; Fortune, S.M. Persisters and beyond: Mechanisms of Phenotypic Drug Resistance and Drug Tolerance in Bacteria. Crit. Rev. Biochem. Mol. Biol. 2014, 49, 91–101. [Google Scholar] [CrossRef]
  86. Wood, T.K.; Knabel, S.J.; Kwan, B.W. Bacterial Persister Cell Formation and Dormancy. Appl. Environ. Microbiol. 2013, 79, 7116–7121. [Google Scholar] [CrossRef]
  87. Wainwright, J.; Hobbs, G.; Nakouti, I. Persister Cells: Formation, Resuscitation and Combative Therapies. Arch. Microbiol. 2021, 203, 5899–5906. [Google Scholar] [CrossRef]
  88. Barman, S.; Kurnaz, L.B.; Leighton, R.; Hossain, M.W.; Decho, A.W.; Tang, C. Intrinsic Antimicrobial Resistance: Molecular Biomaterials to Combat Microbial Biofilms and Bacterial Persisters. Biomaterials 2024, 311, 122690. [Google Scholar] [CrossRef]
  89. Liu, S.; Brul, S.; Zaat, S.A.J. Bacterial Persister-Cells and Spores in the Food Chain: Their Potential Inactivation by Antimicrobial Peptides (AMPs). Int. J. Mol. Sci. 2020, 21, 8967. [Google Scholar] [CrossRef]
  90. Libardo, M.D.J.; Bahar, A.A.; Ma, B.; Fu, R.; McCormick, L.E.; Zhao, J.; McCallum, S.A.; Nussinov, R.; Ren, D.; Angeles-Boza, A.M.; et al. Nuclease Activity Gives an Edge to Host-defense Peptide Piscidin 3 over Piscidin 1, Rendering It More Effective against Persisters and Biofilms. FEBS J. 2017, 284, 3662–3683. [Google Scholar] [CrossRef]
  91. Miao, F.; Tai, Z.; Wang, Y.; Zhu, Q.; Fang, J.K.-H.; Hu, M. Tachyplesin I Analogue Peptide as an Effective Antimicrobial Agent against Candida albicans—Staphylococcus aureus Poly-Biofilm Formation and Mixed Infection. ACS Infect. Dis. 2022, 8, 1839–1850. [Google Scholar] [CrossRef]
  92. Safronova, V.N.; Panteleev, P.V.; Sukhanov, S.V.; Toropygin, I.Y.; Bolosov, I.A.; Ovchinnikova, T.V. Mechanism of Action and Therapeutic Potential of the β-Hairpin Antimicrobial Peptide Capitellacin from the Marine Polychaeta Capitella Teleta. Mar. Drugs 2022, 20, 167. [Google Scholar] [CrossRef]
  93. Jiang, Y.-H.; Xin, W.-G.; Zhang, Q.-L.; Lin, L.-B.; Deng, X.-Y. A Novel Bacteriocin Against Shigella flexneri from Lactiplantibacillus plantarum Isolated from Tilapia Intestine: Purification, Antibacterial Properties and Antibiofilm Activity. Front. Microbiol. 2022, 12, 779315. [Google Scholar] [CrossRef]
  94. Balan, S.S.; Kumar, C.G.; Jayalakshmi, S. Pontifactin, a New Lipopeptide Biosurfactant Produced by a Marine Pontibacter korlensis Strain SBK-47: Purification, Characterization and Its Biological Evaluation. Process Biochem. 2016, 51, 2198–2207. [Google Scholar] [CrossRef]
  95. Xiu, P.; Liu, R.; Zhang, D.; Sun, C. Pumilacidin-Like Lipopeptides Derived from Marine Bacterium Bacillus sp. Strain 176 Suppress the Motility of Vibrio Alginolyticus. Appl. Environ. Microbiol. 2017, 83, e00450-17. [Google Scholar] [CrossRef]
  96. Kiran, G.S.; Priyadharsini, S.; Sajayan, A.; Priyadharsini, G.B.; Poulose, N.; Selvin, J. Production of Lipopeptide Biosurfactant by a Marine Nesterenkonia sp. and Its Application in Food Industry. Front. Microbiol. 2017, 8, 1138. [Google Scholar] [CrossRef]
  97. Qader, M.M.; Hamed, A.A.; Soldatou, S.; Abdelraof, M.; Elawady, M.E.; Hassane, A.S.I.; Belbahri, L.; Ebel, R.; Rateb, M.E. Antimicrobial and Antibiofilm Activities of the Fungal Metabolites Isolated from the Marine Endophytes Epicoccum nigrum M13 and Alternaria alternata 13A. Mar. Drugs 2021, 19, 232. [Google Scholar] [CrossRef]
  98. Rekha, R.; Vaseeharan, B.; Ishwarya, R.; Anjugam, M.; Alharbi, N.S.; Kadaikunnan, S.; Khaled, J.M.; Al-anbr, M.N.; Govindarajan, M. Searching for Crab-Borne Antimicrobial Peptides: Crustin from Portunus pelagicus Triggers Biofilm Inhibition and Immune responses of Artemia salina against GFP Tagged Vibrio parahaemolyticus Dahv2. Mol. Immunol. 2018, 101, 396–408. [Google Scholar] [CrossRef]
  99. Sivakamavalli, J.; Arthur James, R.; Park, K.; Kwak, I.-S.; Vaseeharan, B. Purification of WAP Domain-Containing Antimicrobial Peptides from Green Tiger Shrimp Peaneaus semisulcatus. Microb. Pathog. 2020, 140, 103920. [Google Scholar] [CrossRef]
  100. Sable, R.; Parajuli, P.; Jois, S. Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications. Mar. Drugs 2017, 15, 124. [Google Scholar] [CrossRef]
  101. Torres, M.D.T.; Cao, J.; Franco, O.L.; Lu, T.K.; De La Fuente-Nunez, C. Synthetic Biology and Computer-Based Frameworks for Antimicrobial Peptide Discovery. ACS Nano 2021, 15, 2143–2164. [Google Scholar] [CrossRef]
  102. Taheri-Araghi, S. Synergistic Action of Antimicrobial Peptides and Antibiotics: Current Understanding and Future Directions. Front. Microbiol. 2024, 15, 1390765. [Google Scholar] [CrossRef]
  103. Bolosov, I.A.; Kalashnikov, A.A.; Panteleev, P.V.; Ovchinnikova, T.V. Analysis of Synergistic Effects of Antimicrobial Peptide Arenicin-1 and Conventional Antibiotics. Bull. Exp. Biol. Med. 2017, 162, 765–768. [Google Scholar] [CrossRef]
  104. Choi, H.; Lee, D.G. Synergistic Effect of Antimicrobial Peptide Arenicin-1 in Combination with Antibiotics against Pathogenic Bacteria. Res. Microbiol. 2012, 163, 479–486. [Google Scholar] [CrossRef]
  105. Shi, W.; Chen, F.; Zou, X.; Jiao, S.; Wang, S.; Hu, Y.; Lan, L.; Tang, F.; Huang, W. Design, Synthesis, and Antibacterial Evaluation of Vancomycin-LPS Binding Peptide Conjugates. Bioorganic Med. Chem. Lett. 2021, 45, 128122. [Google Scholar] [CrossRef]
  106. Chu, H.; Pazgier, M.; Jung, G.; Nuccio, S.-P.; Castillo, P.A.; De Jong, M.F.; Winter, M.G.; Winter, S.E.; Wehkamp, J.; Shen, B.; et al. Human α-Defensin 6 Promotes Mucosal Innate Immunity Through Self-Assembled Peptide Nanonets. Science 2012, 337, 477–481. [Google Scholar] [CrossRef]
  107. González, R.; Brokordt, K.; Cárcamo, C.B.; Coba De La Peña, T.; Oyanedel, D.; Mercado, L.; Schmitt, P. Molecular Characterization and Protein Localization of the Antimicrobial Peptide Big Defensin from the Scallop Argopecten purpuratus after Vibrio splendidus Challenge. Fish Shellfish Immunol. 2017, 68, 173–179. [Google Scholar] [CrossRef]
  108. Luo, G.; Sun, Y.; Zhang, J.; Xu, Z.; Lu, W.; Wang, H.; Zhang, Y.; Li, H.; Mao, Z.; Ye, S.; et al. Nanodefensin-Encased Hydrogel with Dual Bactericidal and pro-Regenerative Functions for Advanced Wound Therapy. Theranostics 2021, 11, 3642–3660. [Google Scholar] [CrossRef]
  109. Ribeiro, K.L.; Frías, I.A.M.; Franco, O.L.; Dias, S.C.; Sousa-Junior, A.A.; Silva, O.N.; Bakuzis, A.F.; Oliveira, M.D.L.; Andrade, C.A.S. Clavanin A-Bioconjugated Fe 3 O 4/Silane Core-Shell Nanoparticles for Thermal Ablation of Bacterial Biofilms. Colloids Surf. B Biointerfaces 2018, 169, 72–81. [Google Scholar] [CrossRef]
  110. Mygind, P.H.; Fischer, R.L.; Schnorr, K.M.; Hansen, M.T.; Sönksen, C.P.; Ludvigsen, S.; Raventós, D.; Buskov, S.; Christensen, B.; De Maria, L.; et al. Plectasin Is a Peptide Antibiotic with Therapeutic Potential from a Saprophytic Fungus. Nature 2005, 437, 975–980. [Google Scholar] [CrossRef]
  111. Ahmed, I.; Asgher, M.; Sher, F.; Hussain, S.; Nazish, N.; Joshi, N.; Sharma, A.; Parra-Saldívar, R.; Bilal, M.; Iqbal, H. Exploring Marine as a Rich Source of Bioactive Peptides: Challenges and Opportunities from Marine Pharmacology. Mar. Drugs 2022, 20, 208. [Google Scholar] [CrossRef]
  112. Papon, N.; Copp, B.R.; Courdavault, V. Marine Drugs: Biology, Pipelines, Current and Future Prospects for Production. Biotechnol. Adv. 2022, 54, 107871. [Google Scholar] [CrossRef]
  113. Zhang, B.; Zhao, M.; Tian, J.; Lei, L.; Huang, R. Novel Antimicrobial Agents Targeting the Streptococcus mutans Biofilms Discovery through Computer Technology. Front. Cell. Infect. Microbiol. 2022, 12, 1065235. [Google Scholar] [CrossRef]
  114. Torres, M.D.T.; De La Fuente-Nunez, C. Toward Computer-Made Artificial Antibiotics. Curr. Opin. Microbiol. 2019, 51, 30–38. [Google Scholar] [CrossRef]
  115. Zhang, Q.-T.; Liu, Z.-D.; Wang, Z.; Wang, T.; Wang, N.; Wang, N.; Zhang, B.; Zhao, Y.-F. Recent Advances in Small Peptides of Marine Origin in Cancer Therapy. Mar. Drugs 2021, 19, 115. [Google Scholar] [CrossRef]
  116. Ucak, I.; Afreen, M.; Montesano, D.; Carrillo, C.; Tomasevic, I.; Simal-Gandara, J.; Barba, F.J. Functional and Bioactive Properties of Peptides Derived from Marine Side Streams. Mar. Drugs 2021, 19, 71. [Google Scholar] [CrossRef]
  117. Cappello, E.; Nieri, P. From Life in the Sea to the Clinic: The Marine Drugs Approved and under Clinical Trial. Life 2021, 11, 1390. [Google Scholar] [CrossRef]
  118. Ghareeb, M.A.; Tammam, M.A.; El-Demerdash, A.; Atanasov, A.G. Insights about Clinically Approved and Preclinically Investigated Marine Natural Products. Curr. Res. Biotechnol. 2020, 2, 88–102. [Google Scholar] [CrossRef]
  119. Alves, C.; Silva, J.; Pinteus, S.; Gaspar, H.; Alpoim, M.C.; Botana, L.M.; Pedrosa, R. From Marine Origin to Therapeutics: The Antitumor Potential of Marine Algae-Derived Compounds. Front. Pharmacol. 2018, 9, 777. [Google Scholar] [CrossRef]
  120. Anjum, K.; Abbas, S.Q.; Akhter, N.; Shagufta, B.I.; Shah, S.A.A.; Hassan, S.S.U. Emerging Biopharmaceuticals from Bioactive Peptides Derived from Marine Organisms. Chem. Biol. Drug Des. 2017, 90, 12–30. [Google Scholar] [CrossRef]
  121. Cheung, R.; Ng, T.; Wong, J. Marine Peptides: Bioactivities and Applications. Mar. Drugs 2015, 13, 4006–4043. [Google Scholar] [CrossRef]
  122. Martins, A.; Vieira, H.; Gaspar, H.; Santos, S. Marketed Marine Natural Products in the Pharmaceutical and Cosmeceutical Industries: Tips for Success. Mar. Drugs 2014, 12, 1066–1101. [Google Scholar] [CrossRef]
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Figure 1. Antimicrobial peptides (AMPs) included in the Antimicrobial Peptide Database 3 (APD3) as of December 2024. (a) Distribution of the 5099 peptides according to their synthesis mechanism; (b) Distribution of AMPs according to different natural sources [10].
Figure 1. Antimicrobial peptides (AMPs) included in the Antimicrobial Peptide Database 3 (APD3) as of December 2024. (a) Distribution of the 5099 peptides according to their synthesis mechanism; (b) Distribution of AMPs according to different natural sources [10].
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Figure 2. Effect of membrane-acting marine-derived antimicrobial peptides (AMPs). (a) Toroidal Pore Model: AMPs gather around the membrane forming a ring-shaped hole; (b) Barrel-Stave Model: AMPs’ multimers are able to penetrate the bacterial cell and establish channels that compromise membrane integrity and can also trigger apoptosis; (c) Carpet-like Model: AMPs act along the membrane surface to dissolve the phospholipidic bilayer.
Figure 2. Effect of membrane-acting marine-derived antimicrobial peptides (AMPs). (a) Toroidal Pore Model: AMPs gather around the membrane forming a ring-shaped hole; (b) Barrel-Stave Model: AMPs’ multimers are able to penetrate the bacterial cell and establish channels that compromise membrane integrity and can also trigger apoptosis; (c) Carpet-like Model: AMPs act along the membrane surface to dissolve the phospholipidic bilayer.
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Table 1. AMPs from marine sources with activity against multidrug-resistant bacteria. Abbreviations: MBIC, minimum biofilm inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.
Table 1. AMPs from marine sources with activity against multidrug-resistant bacteria. Abbreviations: MBIC, minimum biofilm inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.
CompoundSourceMechanism of ActionAntibacterial ActivityReferences
PleurocidinWinter flounder (Pleuronectes
americanus)		Membrane disruption, alteration of bacterial metabolic pathways and interference with quorum sensingActive against multi-drug-resistant Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii (MIC values of 8–256 μg/mL)[42,43,44,45,46,47]
ClavaninsLeathery
sea squirt
(Styelaclava)		When paired with Zn2+ ions there is an increased positive charge and membrane affinity, and therefore in membrane disruption abilityActive against MRSA ATCC 43300; MIC values of 16 μg/mL for clavanin C and 64 μg/mL for clavanin E[48,49,50,51,52]
Clavanin D and Clavaspirin can translocate inside the cells without damaging the membrane suggesting that they can interfere with processes inside the bacterial cellActive against multi-drug-resistant Enterobacter cloacae when clavanin D is paired with clavaspirin
Epinecidin-1Grouper (Epinephelus
coioides)		Membrane disruption and immunomodulationActive against MRSA in mouse and pig models, Helicobacter pylori, and P. aeruginosa[53,54,55,56,57]
Tilapia
piscidin-3		Nile tilapia
(Oreochromis
niloticus)		Membrane disruptionActive against MRSA in mouse peritonitis models (≤40 μg/mL)[58,59,60]
Tilapia
piscidin-4		Nile tilapia
(Oreochromis
niloticus)		Membrane disruption and immunomodulationActive against MRSA, carbapenem-resistant A. baumannii and resistant K. pneumoniae in vitro and MRSA in wound and peritonitis models (≤6.25 μg/mL)[58,60,61]
Table 3. Potential strategies to bypass administration challenges of AMPs [35,43]. Abbreviations: AMP, Antimicrobial Peptide; NDEFgel, Nanodefensin-encased hydrogel.
Table 3. Potential strategies to bypass administration challenges of AMPs [35,43]. Abbreviations: AMP, Antimicrobial Peptide; NDEFgel, Nanodefensin-encased hydrogel.
StrategyMode of ActionExamplesReferences
AMP-antibiotic conjugatesCombination of antibiotics with membrane-interfering AMPsColistin and Bacteriocin Ampicilin and Arenin-I Vancomycin and LPS binding peptides[34]
[17,102,103,104]
[105]
NanonetworksNet-like meshwork of fibrils that entangled the bacteriaHuman α-defensin 6 ApBD1[106]
[107]
Nanoparticle-based drug delivery systemsNanomaterials and hydrogels that can amplify the antibacterial spectrum and antimicrobial capacity of AMPsNanodefensin-encased hydrogel (NDEFgel)[108,109]
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Magalhães, R.; Mil-Homens, D.; Cruz, S.; Oliveira, M. Marine Antimicrobial Peptides: Emerging Strategies Against Multidrug-Resistant and Biofilm-Forming Bacteria. Antibiotics 2025, 14, 808. https://doi.org/10.3390/antibiotics14080808

AMA Style

Magalhães R, Mil-Homens D, Cruz S, Oliveira M. Marine Antimicrobial Peptides: Emerging Strategies Against Multidrug-Resistant and Biofilm-Forming Bacteria. Antibiotics. 2025; 14(8):808. https://doi.org/10.3390/antibiotics14080808

Chicago/Turabian Style

Magalhães, Rita, Dalila Mil-Homens, Sónia Cruz, and Manuela Oliveira. 2025. "Marine Antimicrobial Peptides: Emerging Strategies Against Multidrug-Resistant and Biofilm-Forming Bacteria" Antibiotics 14, no. 8: 808. https://doi.org/10.3390/antibiotics14080808

APA Style

Magalhães, R., Mil-Homens, D., Cruz, S., & Oliveira, M. (2025). Marine Antimicrobial Peptides: Emerging Strategies Against Multidrug-Resistant and Biofilm-Forming Bacteria. Antibiotics, 14(8), 808. https://doi.org/10.3390/antibiotics14080808

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