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Review

Antimicrobial Peptides and Their Potential Applications in Plant Protection

by
Deming Sun
1,†,
Zhaohui Jia
1,†,
Junjie Zhu
1,
Jinhua Liu
2,
Yichao Chen
3,
Zhi Xu
4,* and
Haijie Ma
1,*
1
Key Laboratory of Quality and Safety Control for Subtropical Fruit and Vegetable, Ministry of Agriculture and Rural Affairs, Collaborative Innovation Center for Efficient and Green Production of Agriculture in Mountainous Areas of Zhejiang Province, College of Horticulture Science, Zhejiang A&F University, Hangzhou 311300, China
2
Natural Medicine Institute of Zhejiang YangShengTang Co., Ltd., Hangzhou 311300, China
3
Wenzhou Vocational College of Science and Technology, Wenzhou 325006, China
4
Analysis and Test Center, Hainan Provincial Key Laboratory of Quality and Safety for Tropical Fruits and Vegetables, Key Laboratory of Quality and Safety Control for Subtropical Fruit and Vegetable, Key Laboratory of Tropical Fruits and Vegetables Quality and Safety for State Market Regulation, Chinese Academy of Tropical Agricultural Sciences, Haikou 570311, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Agronomy 2025, 15(5), 1113; https://doi.org/10.3390/agronomy15051113
Submission received: 23 March 2025 / Revised: 22 April 2025 / Accepted: 30 April 2025 / Published: 30 April 2025
(This article belongs to the Special Issue Research Progress on Pathogenicity of Fungi in Crops—2nd Edition)
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Abstract

:
The overuse of pesticides has led to resistance in phytopathogens, posing significant threats to global food security and environmental health. Antimicrobial peptides (AMPs), small molecules produced by various organisms as part of their innate immune defense, exhibit broad-spectrum antimicrobial activity with a lower risk of resistance development. These properties make AMPs promising candidates for sustainable agricultural practices. However, challenges such as high production costs, instability, and potential toxicity to plant cells have hindered their widespread application. This review provides a comprehensive overview of the discovery, classification, and antimicrobial mechanisms of AMPs, focusing on their roles in plant protection. It also explores strategies for identifying and optimizing AMPs, including structural modifications, targeted delivery systems, and production methods using plant- and microbe-based expression systems. Additionally, the review highlights the potential of transgenic approaches to enhance crop resistance by expressing AMP genes in plants. Despite the challenges, AMPs offer a transformative opportunity for modern agriculture, providing innovative solutions to combat plant diseases while reducing reliance on conventional pesticides. Continued research and technological advancements are essential to fully realize the potential of AMPs in sustainable plant protection.

1. Introduction

Pathogenic bacteria, fungi, viruses, and oomycetes cause severe diseases in natural ecosystems and agriculture, threatening plant biodiversity and food security worldwide. Overuse of pesticides has accelerated pathogen resistance, spurring research into alternative solutions. Antimicrobial peptides (AMPs) are a diverse group of small molecules widely found in nature, forming a crucial part of the innate immune system in organisms [1]. They effectively combat various bacteria and also possess antifungal, antiviral, and antiparasitic activities, primarily by disrupting the structure and function of cell membranes [2]. Therefore, AMPs are widely applied across various fields, such as medicine, agriculture, and food [3,4,5]. In agriculture, they show great potential for applications such as managing plant diseases, enhancing plant disease resistance, developing disease-resistant crops, and prolonging the shelf life of agricultural products [6,7,8,9,10]. This review summarizes and analyzes the identification, classification, mechanism, screening, optimization, production, and application of AMPs in plant protection, aiming to offer insights for advancing plant disease management, breeding disease-resistant crops, and developing novel antibiotics.

2. The Discovery History of AMPs

In 1922, Alexander Fleming first identified a soluble antimicrobial substance produced by humans, later named lysozyme [11]. Subsequently, Fleming’s discovery of penicillin in 1928, followed by its therapeutic use in the 1940s, for which he was awarded the Nobel Prize in Medicine in 1945, shifted attention away from the therapeutic potential of natural AMPs. Over recent decades, the overuse of antibiotics has resulted in a significant rise in bacterial resistance, creating an urgent need for alternative treatments [12]. Consequently, AMPs have gained increased attention due to their broad-spectrum and effective antibacterial properties. In 1939, René Dubos isolated gramicidin from the culture supernatant of soil bacteria, which was later shown to be a heterogeneous mixture of six AMPs and exhibited bactericidal or bacteriostatic activity against a wide range of Gram-positive bacteria [13]. Gramicidins were the first AMPs for which the primary structures were characterized and the first antibiotics to be commercially produced [14]. In 1941, the AMP of tyrocidine was discovered and found effective against bacteria. The first member of the AMP family of thionin, purothionin, was isolated from wheat endosperm Triticum aestivum in 1942 and demonstrated inhibitory effects against Pseudomonas solanacearum and Xanthomonas campestris [15]. The first animal-derived AMP to be reported was defensin, which was isolated from rabbit leukocytes in 1956 [16]. In the subsequent years, bombinin from epithelial cells and lactoferrin from cow milk were both documented [17]. Concurrently, it was also substantiated that human leukocytes harbor AMPs within their lysosomes [18]. In the 1970s, advancements in separation, analysis, and sequencing techniques significantly influenced the discovery of AMPs. The introduction of HPLC greatly improved resolution, reproducibility, and sensitivity, establishing reversed-phase HPLC as a widely used method for peptide separation. In 1980, a new class of AMPs called cecropins was discovered in the pupae of the cecropia moth Hyalophora cecropia, exhibiting bacteriolytic activity against both Gram-negative and Gram-positive bacteria [19]. Although cecropins were first discovered in insects, later studies have revealed their widespread presence throughout the animal kingdom [20]. It is now known that the majority of organisms are capable of synthesizing AMPs. AMPs play a crucial role in the innate immune response against pathogenic bacterial infections in humans and other higher organisms, serving as the primary defense mechanism against various pathogenic microorganisms [1,21]. Among plant defense molecules, AMPs represent a prevalent and prominent chemical barrier that plants have evolved to effectively combat biotic stresses [22]. The first plant-derived AMP was isolated and shown to be active against a range of bacterial pathogens, including Corynebacterium flaccumfaciens, C. fascians, C. michiganense, C. poinsettiae, C. sepedonicum, Erwinia amylovora, Pseudomonas solanacearum, Xanthomonas phaseoli, and X. campestris [23,24]. Since then, several AMPs have been discovered, with major group including defensins, thionins (types I–V), 2S albumin-like proteins, cyclotides, and lipid transfer proteins, along with less common AMPs such as glycine-rich, heveins, impatiens, knottin-peptides, puroindolines, shepherins, snakins, and vicilin-like peptides [25,26,27,28,29]. In recent years, a series of studies have found that overexpressing AMPs in transgenic plants can effectively inhibit the proliferation of pathogens within the host [30,31,32,33,34,35]. Moreover, the application of exogenous AMPs for controlling plant diseases has also proven to be effective [8] (Figure 1).

3. Classification of AMPs

Most AMPs are oligopeptides consisting of 5 to 100 amino acids, typically carrying a positive net charge (+2 to +11) and containing a high proportion (around 50%) of hydrophobic residues [36,37]. By 2024, over 8000 AMPs have been documented. The diversity of natural AMPs complicates their classification, which can be based on their source, structural characteristics, activity, and amino acid-rich species.

3.1. Source-Based Classification of AMPs

The sources of AMPs can be categorized into animals, plants, fungi, protists, archaea, bacteria, and synthetic origins according to statistical data from APD3 [https://aps.unmc.edu/ (accessed on 22 April 2025)]. The animals include mammals, invertebrates, fish, amphibians, reptiles, and birds. The predominant mammalian AMPs are members of the cathelicidin and defensin families, though other AMPs, such as platelet antimicrobial proteins, hepcidins, and dermcidin, also exist outside these two families [38,39]. Invertebrates, lacking an adaptive immune response, produce AMPs as a crucial component of their humoral defense system [40,41]. Among natural AMPs with known antimicrobial activity, amphibians are the largest source in APD3, with over 1000 entries from frogs and toads. Most bacteriocins isolated from Gram-negative bacteria have been reported in E. coli, although other species like Pseudomonas spp. and Klebsiella spp. also produce AMPs, which are active against Gram-negative organisms with a narrow spectrum [42]. In Gram-positive bacteria, AMPs are synthesized both ribosomally and non-ribosomally, with ribosomally produced AMPs known as bacteriocins [43]. These peptides target bacteria closely related to the producing strain and are classified into four classes: large-sized bacteriocins, non-lantibiotics, lantibiotics, and uniquely structured bacteriocins [42,44]. Fungi are a rich source of AMPs, producing peptides with broad-spectrum antimicrobial activity. Some well-known fungal AMPs include defensins, which function by disrupting microbial cell membranes or inhibiting cell wall synthesis. Synthetic AMPs typically refer to peptides that are artificially designed and produced through chemical synthesis methods. With advancements in technology, the design of these peptides has become increasingly precise, enabling researchers to optimize their structures and functions based on natural templates. This optimization enhances their antimicrobial activity against specific pathogens. The advantages of synthetic AMPs include overcoming the limitations of natural peptides and offering flexibility for modifications and adjustments tailored to specific needs in combating pathogens (Figure 2).

3.2. Structure-Based Classification of AMPs

AMPs can be broadly divided into four structural categories: α-helical, β-sheet, extended, and cyclic [45,46,47] (Figure 3). Natural AMPs typically consist of 5 to 100 amino acid residues, with the majority being under 50 amino acids [48]. Peptide length significantly influences antimicrobial activity, as shorter peptides often fail to form essential secondary structures like α-helices and β-sheets [49,50]. Among these AMP groups, α-helix peptides are the most extensively studied. Their α-helix motifs are critical for interacting with and disrupting target membranes. Altering the α-helical structure, such as through amino acid substitutions, significantly reduces their antibacterial activity. The second group of AMPs adopts a β-sheet conformation, composed of at least two β-strands linked by disulfide bonds. These disulfide bridges are essential for structural stabilization and biological function. Additional stability arises from salt bridges and head-to-tail cyclization. Due to their stable structure, β-sheet AMPs maintain their conformation upon interacting with phospholipid membranes [51]. Typically, they exhibit amphipathic properties, with β-strands forming distinct polar and non-polar domains [52]. Cyclic peptides are composed of amino acids linked in a circular structure, which gives them increased stability and resistance to enzymatic degradation. Their ring structure can enhance their binding affinity to targets, improving their antimicrobial and therapeutic potential. These peptides often have specific hydrophilic or hydrophobic properties, depending on the amino acid composition, and are widely used in drug design due to their selective binding and enhanced biological activity. Additionally, their biological activity depends on key factors such as charge, helicity, hydrophobicity, sequence, and solubility [53].

3.3. Activity-Based Classification of AMPs

The APD3 database categorizes AMPs into 25 types based on their activity. These can be summarized into five categories here: antibacterial, antifungal, antiviral, antiparasitic, anti-tumor, and others [54]. Antibacterial peptides (ABPs) represent a significant subset of AMPs, exhibiting broad-spectrum inhibition against pathogenic bacteria, including Staphylococcus aureus in food and Vibrio parahaemolyticus in aquaculture. Natural and synthetic ABPs, such as cecropins and defensins, effectively target Gram-positive and Gram-negative bacteria. Antifungal peptides (AFPs) combat drug-resistant fungal infections, including Candida albicans in medicine and Aspergillus flavus in agriculture. For example, the AFP (FPSHTGMSVPPP) inhibits A. flavus MD3 growth, while peptides from Lactobacillus plantarum reduce spore formation in maize [55]. Antiviral peptides target viruses by preventing attachment, fusion, replication, or destroying the virus envelope [56]. Meanwhile, antiparasitic peptides like cathelicidin and temporins exhibit strong inhibition activity against parasites [57]. However, the mechanisms of action of different antiparasitic peptides may vary. For example, cyanobacterial peptides uniquely target specific proteins, allowing for precise parasite discrimination, even within similar genera [58].

3.4. Classification of AMPs Based on Amino Acid-Rich Species

Proline-rich AMPs (PrAMPs) enter bacterial cytoplasm through the SbmA transporter rather than by membrane disruption [59]. Inside the cell, they interfere with protein synthesis by targeting ribosomes, blocking aminoacyl-tRNA binding, or trapping decoding release factors during translation termination [60]. While primarily effective against Gram-positive bacteria, PrAMPs like pPR-AMP1 from crabs exhibit activity against both Gram-positive and Gram-negative bacteria [61]. Tryptophan (Trp), a non-polar amino acid, affects the lipid bilayer interface, while arginine (Arg), a basic amino acid, contributes to peptide charge and forms hydrogen bonding with bacterial membranes. Trp enhances Arg-rich AMP interactions with membranes through ion-pair interactions. Notable AMPs, such as indolicidin and triptrpticin, are rich in Arg and Trp. Histidine-rich AMPs, such as HV2, show excellent membrane permeation activity, causing bacterial cell membrane rupture and death. L4H4, derived from magainin, exhibits strong antibacterial and cell penetration properties due to the insertion of histidine sequences [62]. Glycine-rich AMPs, like attacins and diptericins, contain 14–22% glycine, which affects their tertiary structure. Cysteine-rich AMPs, integral to plant defense systems, contain multiple disulfide bridges (ranging from 2 to 6), which create a compact conformation and provide stability against thermal, chemical, and proteolytic degradation [63].

4. Antimicrobial Mechanisms of AMPs

AMPs exert their effects through two primary mechanisms. The first involves disrupting the structural integrity of microbial cell membranes, a feature characteristic of membrane-targeting AMPs. The second mechanism includes non-membrane-targeting AMPs, which inhibit key microbial processes such as protein and nucleic acid synthesis, enzymatic activity, and cell division [64,65].

4.1. Membrane-Targeting Mechanism

The physicochemical properties of AMPs, such as net charge, hydrophobicity, amphipathicity, membrane curvature, and self-aggregation tendency, are crucial in modulating peptide–membrane interactions [66]. Most AMPs are positively charged, targeting bacterial cytoplasmic membranes rich in anionic lipids, as well as negatively charged surface components such as teichoic acids, lipoteichoic acids, and lipopolysaccharides (LPS). Therefore, electrostatic attraction serves as a critical driving force for the initial binding of AMPs to the bacterial cell surface [51,53]. The hydrophobicity of AMPs determines their interaction with the fatty acyl chains of membrane lipids, facilitating peptide insertion into the hydrophobic core of the bilayer [67]. Amphipathicity, defined by the distribution of hydrophobic and hydrophilic residues on opposite sides of the peptide chain, influences the binding affinity of α-helical AMPs to membranes. Moreover, the membrane topography, influenced by lipid composition, also plays a role. AMPs tend to embed within membranes with positive spontaneous curvature, whereas in membranes with negative spontaneous curvature, they are more likely to remain in a surface-bound state. As the AMP concentration on the membrane increases, peptide–peptide or lipid–peptide complexes form. Once a critical aggregation concentration is reached, AMPs penetrate the bilayer’s hydrophobic core, creating transmembrane pores in the cytoplasmic membrane [68].
The membrane-targeting mechanisms of AMPs primarily include the carpet, barrel-stave, toroidal pore, and aggregate channel models. In the carpet model, AMPs bind parallel to the membrane surface via interactions with negatively charged phospholipid heads. Upon reaching a critical concentration, AMPs reorient, forming hydrophobic-core micelles that disintegrate the membrane [69] (Figure 4). In the barrel-stave model, AMPs adsorb on the membrane surface and rotate perpendicularly into the bilayer upon reaching a critical concentration. This forms transmembrane channels, causing cytoplasmic outflow [70]. In severe cases, AMPs cause membrane collapse and cell death [71]. In the toroidal model, AMPs are vertically inserted into the cell membrane, where they accumulate and bend to form a toroidal pore with a diameter of 1–2 nm [72]. In the aggregate channel model, AMPs randomly aggregate on the cell membrane surface. Upon reaching a certain concentration, they form peptide–lipid complexes, which disrupt the lipid bilayer in a detergent-like manner, creating dynamic transmembrane pores. The membrane-targeting mechanisms of AMPs exploit differences in lipid composition across bacterial and fungal cell membranes. Bacteria primarily contain anionic lipids like phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL), while fungi have phosphatidylcholine (PC), phosphatidylinositol (PI), and ergosterol. Fungal membranes are more anionic and contain higher PC levels compared to mammalian membranes, which are cholesterol-based. These compositional differences allow AMPs to selectively target microbial membranes.

4.2. Non-Membrane-Targeting Mechanism

In addition to targeting the membrane, some AMPs can act on intracellular components, disrupting cellular functions and ultimately leading to cell death. These non-membrane-targeting mechanisms encompass the inhibition of nucleic acid and protein biosynthesis, suppression of protease activity and cell division, as well as protein degradation [64,73]. AMPs inhibit protein biosynthesis by targeting transcription, translation, and molecular chaperone-mediated folding. For example, Bac7 and Tur1A disrupt ribosomal function [74], while DM3 affects multiple intracellular pathways [75]. AMPs inhibit nucleic acid biosynthesis by targeting enzymes, degrading DNA/RNA, or crosslinking DNA [76]. Some AMPs can inhibit metabolic activities by targeting enzyme functions, exemplified by histatin-5 and cathelicidin-BF [77,78]. AMPs inhibit cell division through DNA replication interference, DNA damage response inhibition, or cell cycle disruption [79,80] (Figure 5).

5. Strategies for AMP Identification and Improvement

5.1. Identification of AMPs

Advancements in technology have led to the identification of an increasing number of AMPs. Researchers have established several AMP databases, such as APD3, CAMPR3, and DBAASP, to facilitate AMP research (Table 1). These databases are periodically updated to include newly identified AMPs. Currently, AMP identification methods can be broadly classified into traditional experimental approaches, as well as bioinformatics and omics-based strategies. Details are as follows.

5.1.1. Traditional and Experimental Approaches

AMPs were initially identified through extraction from natural sources such as plants, insects, amphibians, marine organisms, and microorganisms. Conventional methods, including high-performance liquid chromatography (HPLC), mass spectrometry (MS), and minimum inhibitory concentration (MIC) assays, have been instrumental in characterizing their structure and antimicrobial efficacy [87,88]. However, these approaches are labor-intensive, sample-demanding, and limited in throughput. Recent advances, such as phage display and combinatorial peptide libraries, have enabled the high-throughput screening of vast peptide repertoires, facilitating the identification of novel AMPs with enhanced antimicrobial properties and reduced cytotoxicity [89,90].

5.1.2. Bioinformatics and Omics-Based Strategies

With the advent of computational biology, bioinformatics has become a pivotal tool for AMP discovery. Algorithms based on machine learning analyze key physicochemical properties of peptides, such as net charge, hydrophobicity, amphipathicity, and secondary structure, to predict antimicrobial activity [91]. Tools like AntiBP, Deep-AmPEP30, and databases such as APD3 and CAMPR have significantly streamlined AMP identification, providing extensive repositories of experimentally validated peptides [81,92,93]. Concurrently, omics-based approaches have emerged as powerful techniques for AMP discovery. Genomic analyses reveal AMP-encoding genes, while transcriptomics identifies stress-inducible peptides under specific environmental conditions [94,95]. Proteomics further elucidates the post-translational modifications that are critical for AMP functionality [96]. Advances in high-throughput technologies, including next-generation sequencing (NGS) and advanced MS platforms, have augmented the efficiency and scope of these methodologies, enabling the rapid identification of novel AMPs from diverse organisms. Additionally, machine learning has become a powerful tool for designing novel and efficient AMPs [97,98]. By analyzing large datasets of known AMPs, machine learning algorithms can predict peptide sequences with optimized antimicrobial properties. This approach significantly accelerates the discovery of new AMPs, potentially resulting in more effective and targeted antimicrobial agents. However, the practical efficacy of newly identified AMPs in field-based plant protection systems requires rigorous validation through controlled field trials.

5.2. Improvement of AMPs

The potential application of AMPs in agriculture is hindered by challenges such as toxicity to non-target organisms, stability under field conditions, and production costs. In recent years, substantial efforts have been made to modify and enhance AMPs, enabling their more effective utilization in agricultural settings. In this review, we analyze four key strategies for improving AMPs: structural modifications to enhance activity and stability, optimization for targeted delivery, improving selectivity while reducing toxicity, and increasing production efficiency.

5.2.1. Structural Modifications to Enhance Activity and Stability

One of the primary strategies for improving AMPs for agricultural applications is modifying their structure to enhance antimicrobial activity, stability, and selectivity. Key strategies include the following. Amino acid substitution: Substituting hydrophobic and cationic amino acids can enhance AMP binding to microbial membranes, improving activity against plant pathogens [99]. Substitution also allows for a reduction in cytotoxicity to plant cells and non-target organisms. Cyclization: Cyclizing AMPs to form a stable ring structure can protect them from proteolytic degradation, enhancing their stability in soil or when applied to crops [100]. Incorporation of non-natural amino acids: Non-natural amino acids, such as D-amino acids, can be introduced into the peptide sequence to improve resistance to enzymatic degradation, extending the peptide’s activity in the field [101]. For example, derivatives of the cationic AMP Pep05 (KRLFKKLLKYLRKF) were synthesized by substituting L-amino acid residues with D- and unnatural amino acids, and their antimicrobial activities, toxicities, and stabilities against trypsin, plasma proteases, and secreted bacterial proteases were evaluated [102]. Peptide fusion: Fusing AMPs with other molecules, such as plant growth-promoting factors or targeting peptides, can enhance selectivity and improve the therapeutic effects in agricultural applications. For example, fusion with antimicrobial proteins like chitinase or glucanase can synergistically target fungal and bacterial pathogens [103].

5.2.2. Optimization for Targeted Delivery

Improving the delivery and bioavailability of AMPs is essential for their effective use in agriculture. Key strategies include the following. Encapsulation in nanomaterials: Encapsulation of AMPs in nanoparticles or liposomes can improve stability under environmental stresses and enhance their delivery to plant tissues [104,105,106]. Nanomaterials can protect AMPs from degradation and control the release of the peptides in the targeted areas [107]. Previous studies have identified some AMPs with potential agricultural applications when combined with nanotechnology, as listed in Table 2. Transgenic approaches: Genetically modifying crops to express AMPs directly in plant tissues offers a promising way to deliver AMPs to where they are needed, reducing the need for external applications and minimizing the risks of non-target toxicity. For instance, the overexpression of specific AMP in citrus and potato roots via Agrobacterium-mediated genetic transformation markedly decreases the concentration of pathogenic bacteria in the transgenic roots [108]. Sprayable formulations: AMPs can be formulated into sprayable solutions for direct application to crops. For instance, foliar application of the MaSAMP solution [10 μM MaSAMP, 0.5% methylated seed oil surfactant, 1 × PBS (pH 7.3)] could induce the expression of defense-related genes and trigger systemic defense responses in Nicotiana benthamiana and tomato, and effectively suppress the proliferation of Candidatus Liberibacter asiaticus (CLas) in citrus tissues [8]. In addition, improving solubility and reducing degradation during spraying can help maintain the effectiveness of AMPs.

6. Production of AMPs

Reducing the cost of AMP production is essential for their practical application in agriculture. AMPs can be produced using various methods, including plant bioreactors, microbial fermentation, cell culture, chemical synthesis, and insect systems. Among these, microbial fermentation and plant bioreactors stand out as the most suitable approaches for agricultural applications due to their cost-effectiveness and scalability. Key strategies include the following.

6.1. Plant-Based Expression

Expression of AMPs in plants (such as tobacco or Arabidopsis) or plant cell cultures offers a cost-effective and scalable production system. Transgenic plants expressing AMPs can be used for direct application in agriculture or as a source for peptide extraction. To date, numerous AMPs, including ADP2–3, Colicin M, Dermaseptin, Defensin, Protegrin, PaeM4, and Lactostatin, have been successfully expressed and purified from plants [114,115,116,117,118,119,120]. Plant production systems utilize photosynthesis to generate biomass, enabling large-scale AMP production without the need for costly fermentation equipment, while ensuring proper folding to enhance AMP activity and stability [121]. Currently, plant-based AMP production systems can be classified into stable and transient expression systems. The stable expression system is achieved by integrating the AMP gene into either the nuclear or plastid genome [122]. Notably, plastids offer distinct advantages, such as preventing epigenetic transgene silencing and avoiding transmission through pollen [123]. Moreover, integrating AMP genes into the chloroplast genome facilitates high-copy-number expression, enabling chloroplasts to produce significant amounts of foreign proteins [122,124,125,126]. However, the stable expression of AMPs in chloroplasts is constrained by low transformation efficiency and its applicability to a limited number of plant species. Transient expression systems, which utilize plant viruses or Agrobacterium-mediated approaches, enable high-level AMP expression within a short timeframe, with tobacco being the most commonly used platform [114,127,128]. These systems offer the advantages of a rapid production cycle and high expression efficiency, but sustaining long-term expression remains a challenge.
Whether through stable expression systems or transient expression systems, the production of AMPs still faces many similar challenges. The small size and low molecular weight of AMPs render them highly vulnerable to protease digestion within transgenic plants [129,130,131]. Fusion partners have been developed to address these challenges, enhancing AMP stability, expression, and accumulation. For example, in the chloroplast expression system, fusing SUMO with AMPs can improve their solubility, boost their yield, and mitigate their toxicity to tobacco [122]. Additionally, heterologous expression aids purification, boosts peptide efficiency through synergy with fusion partners, and minimizes toxicity to host cells. Inducible expression systems, tissue-specific promoters, and secretion signal peptide strategies have also demonstrated significant positive effects in enhancing AMP yield and reducing AMP toxicity in transgenic plants. In inducible expression systems, AMPs driven by inducible promoters can be expressed under specific conditions, such as after the transgenic plant reaches a certain growth stage through chemical or environmental induction [122]. This approach can mitigate the toxic effects of AMPs on the early growth and development of transgenic plants. For example, the Os.hsp82 promoter exhibits strong induction in response to heat shock [132]. The RAmpER system, entirely chloroplast-based, regulates transgene expression through a theophylline-inducible riboswitch [133,134]. By utilizing tissue-specific promoters, AMPs can be restricted to expression in non-sensitive plant tissues, such as being expressed exclusively in roots or fruit tissues. For example, the use of the endosperm-specific promoter from the barley B1 hordein gene or the maize ubiquitin promoter to express the LL-37 AMP in barley not only ensures that the transgenic plants exhibit normal phenotypes and remain fertile but also achieves LL-37 accumulation in seeds at levels up to 0.55 mg/kg [135]. Secretion signal peptide strategies alleviate toxicity by directing AMPs to the extracellular space, minimizing their accumulation in the cytoplasm where they could interfere with cellular processes. Furthermore, extracellular targeting not only prevents potential toxicity to host cells but also facilitates direct interaction with pathogens residing and proliferating in the extracellular environment. Moreover, the signal peptide is cleaved during processing through the secretory pathway, ensuring minimal or no impact on the activity of the AMPs [136]. Currently, this strategy has been shown to significantly enhance the resistance of plants such as tomato and citrus to pathogens [137,138].

6.2. Bacteria-Based Expression

The microbial production of AMPs has emerged as a prominent research area, with numerous ribosomally and non-ribosomally synthesized peptides identified in recent years [139,140]. Bacterial and yeast expression systems are commonly employed for the heterologous production of molecules with pharmacological and industrial applications. Bacteria, in particular, are favored as hosts due to their ability to grow in cost-effective media, rapid doubling times, and high efficiency in incorporating foreign DNA and producing recombinant proteins. E. coli is a widely used bacterial system for the high-level expression of recombinant peptides, proteins, and membrane proteins [141,142]. Notably, the Protein Data Bank (PDB) reports that over 90% of proteins or peptides are produced using E. coli expression systems [143]. However, bacterial systems have certain limitations, including inefficient secretion mechanisms for peptide release into the growth medium and restricted capabilities for disulfide bond formation, post-translational modifications, and glycosylation [141,144,145]. Engineered E. coli strains with mutations in the glutathione reductase (gor) and thioredoxin reductase (trxB) genes can now correctly fold proteins with multiple disulfide bonds in the cytoplasm [146,147,148,149,150]. Bacillus subtilis, a GRAS (generally regarded as safe)-designated Gram-positive bacterium commonly found in soil and the gastrointestinal tracts of ruminants and humans, is non-pathogenic and capable of secreting enzymes or antibiotics, producing spores, and undergoing genetic transformation [151,152,153]. These features make it a viable alternative to the E. coli expression system, with the highest expression level achieved in the WB30 strain carrying a mutation in the sacUh gene [154]. B. subtilis has proven highly efficient for peptide and protein production, with WB600 strain reaching yields of 20–25 g·L−1 and WB800N strain successfully expressing cathelicidin (CBF) and plectasin with preserved antimicrobial activity [155,156]. Using a SUMO-tagged system, WB800N produced 5.5 mg of purified plectasin per liter at 94% purity, exemplifying the safety and scalability of B. subtilis for peptide production [157]. Continued research seeks to optimize and expand its industrial applications further [151,152,155,158,159,160].

6.3. Yeast-Based Expression

The heterologous production of AMPs in bacteria is hindered by challenges such as host toxicity, instability, protease susceptibility, and the need for expensive post-translational modifications. These limitations have driven the search for alternative microbial expression systems to improve efficiency and cost-effectiveness. Yeasts are organisms with low nutritional demands and offer advantages like rapid growth, genetic simplicity, proper post-translational modifications, and scalable, pathogen-free protein production [161,162,163,164]. Saccharomyces cerevisiae, the first eukaryotic organism used for recombinant protein production, is well studied and GRAS-designated, making it a popular host for producing biologically active proteins under industrial conditions [165,166,167,168,169]. However, limitations such as low protein yields, hyperglycosylation, and fermentative metabolism have constrained its use in AMP production [163,165,169]. Consequently, alternative expression platforms have been developed using various yeast species, including Komagataella phaffii (Pichia pastoris), Hansenula polymorpha, Kluyveromyces lactis, and Schizosaccharomyces pombe, among others [170]. K. phaffii avoids carbon diversion to ethanol production, enabling high biomass and recombinant molecule yields, which are further enhanced by the methanol-induced PAOX1 promoter for efficient heterologous expression [161,163,171,172,173]. While widely used for producing pharmacologically and industrially relevant molecules, its drawbacks, such as proteinase production, can occasionally hinder recombinant production [165]. Proteolysis often occurs during vesicular transport or in the extracellular space, reducing recombinant protein yield and activity [174]. To address this, protease-deficient yeast strains like SMD1163, SMD1165, and SMD1168 are used, though they exhibit slower growth and lower viability compared to wild strains [175]. Despite these challenges, K. phaffii has shown superior performance in AMP production compared to E. coli, with higher yields and enhanced antimicrobial activity due to its ability to perform post-translational modifications. Several AMPs, including scygonadin, vpdef defensin, snakin-1, clavanine, and penaeidine, have been successfully expressed in K. phaffii [176,177,178,179,180]. Inducible promoters like AOX1 are commonly utilized in K. phaffii to achieve high yields, with some peptides reaching concentrations of up to 2390 mg·L−1 [181]. Tandem multimeric expression has further boosted yields, as observed with plectasine and adenoregulin, underscoring the versatility of K. phaffii in optimizing production processes [182,183].

7. Application Strategies of AMPs in Plant Protection

AMPs can be applied in plant protection through various strategies, mainly including direct application and genetic engineering (Table 3). The key approaches are outlined below:

7.1. Direct Application of AMP Products

The direct application of AMPs represents a practical and straightforward strategy for plant disease control, leveraging their rapid antimicrobial activity to combat pathogens. AMPs can be formulated into aqueous or emulsified sprays that are directly applied to plant surfaces, including leaves, stems, and fruits. This approach has demonstrated effectiveness against a range of pathogens, including bacteria and fungi causing diverse plant diseases. For example, the application of SAMP or APP3–14 effectively reduces Candidatus Liberibacter asiaticus (CLas) titer and disease symptoms in HLB-positive citrus, while also inducing plant immune responses, with superior thermal stability compared to antibiotics, making it well suited for field use [8,30]. In tomato, foliar application of a specific AMP at 200 ppm effectively reduces disease incidence by 49.3% and severity by 45.8% [184]. In addition, the application of AMPs has been shown to provide effective control against diseases such as brown spot and powdery mildew [185,186]. Direct AMP application faces challenges like environmental degradation from UV light, heat, and proteases, which can be mitigated by encapsulation technologies such as liposomes or polymer-based carriers to enhance stability [187].

7.2. Plant Expression of AMP Genes

Overexpression of AMPs in plants has been shown to significantly enhance disease resistance. For instance, overexpression of CaAMP1 in soybean improves tolerance to Phytophthora root and stem rot [31]. Similarly, transgenic Brassica rapa plants overexpressing LL-37 exhibit broad-spectrum resistance to bacterial and fungal pathogens, evidenced by smaller disease lesions and increased tolerance. Additionally, the expression of the plant AMP gene pro-SmAMP2 in transgenic potato enhances resistance to Alternaria and Fusarium pathogens. Transgenic plants incorporating AMP genes have also been used to control Alternaria alternata, Alternaria longipes, Alternaria solani, Botrytis cinerea, Heterobasidion annosum, Leptosphaeria maculans, Magnaporthe grisea, Phytophthora parasitica, Verticillium albo-atrum, V. dahliae, Xanthomonas citri subsp. citri, and so on [27,188,189,190,191,192,193,194,195,196]. Despite the clear potential of transgenic crops expressing AMP genes, regulatory challenges and public skepticism limit their widespread adoption. Ensuring their safety and environmental sustainability, along with raising awareness of their role in reducing pesticide use and improving food security, is essential. Furthermore, reducing the toxicity of AMPs to transgenic plants represents a key focus for future research.

8. Conclusions

AMPs hold great promise as an alternative to traditional pesticides, offering broad-spectrum antimicrobial activity, low resistance development potential, and eco-friendly compatibility with sustainable agricultural practices. Beyond their direct antimicrobial properties, AMPs can enhance plant immunity by inducing defense responses, further expanding their utility in crop protection [8]. This review comprehensively explores their discovery, classification, mechanisms of action, production methods, and application strategies in plant protection, highlighting their versatility and potential for agricultural innovations. The diverse mechanisms and types of AMPs allow for various application methods, making them valuable candidates for developing targeted and efficient AMP-based pesticides. Their relatively low cytotoxicity to plant and animal cells and rapid degradation by pepsin reduce environmental and safety concerns, strengthening their suitability for agricultural deployment. Moreover, genetic engineering approaches, such as overexpressing AMP genes in crops, could enable cost-effective and species-specific disease resistance in the future. However, the large-scale application of AMPs in agriculture is limited by several challenges. These include the high costs of production and purification, the need to optimize fermentation and transformation techniques, and the development of AMPs effective against a broader range of plant pathogens, including viruses. Additionally, enhancing the stability and absorption efficiency of AMP formulations remains critical for field application. Despite these obstacles, AMPs represent a transformative opportunity for modern agriculture, offering innovative solutions to combat plant diseases while reducing reliance on conventional pesticides. With continued research and technological advancements, AMPs have the potential to revolutionize plant protection, contributing to a more sustainable and secure global food system. Accelerating efforts to address these challenges will be essential for realizing this vision.

Author Contributions

Writing—original draft preparation, H.M. and D.S.; writing—literature collection, H.M.; writing—review and editing, H.M., D.S., Z.J., J.Z., and Y.C.; supervision, H.M. and Z.X.; funding acquisition, H.M., Z.X. and J.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 32202427), the Natural Science Foundation of Zhejiang Province (No. LY24C150005), and the Open Fund of the Hainan Provincial Key Laboratory of Quality and Safety for Tropical Fruits and Vegetables and Key Laboratory of Quality and Safety Control of Subtropical Fruits and Vegetables, Ministry of Agriculture and Rural Affairs (No. KFKT2024003).

Conflicts of Interest

Author Jinhua Liu was employed by the company Natural Medicine Institute of Zhejiang YangShengTang Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Figure 1. The timeline of AMP discovery and research progress.
Figure 1. The timeline of AMP discovery and research progress.
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Figure 2. The sources of AMPs based on APD3 [https://aps.unmc.edu/ (accessed on 22 April 2025)].
Figure 2. The sources of AMPs based on APD3 [https://aps.unmc.edu/ (accessed on 22 April 2025)].
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Figure 3. Representative structural classes of AMPs.
Figure 3. Representative structural classes of AMPs.
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Figure 4. Activity model of extracellular AMPs.
Figure 4. Activity model of extracellular AMPs.
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Figure 5. Schematic representation of non-membrane-targeting mechanism.
Figure 5. Schematic representation of non-membrane-targeting mechanism.
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Table 1. Information of AMP databases.
Table 1. Information of AMP databases.
No.DatabaseIntroductionURLAMP Count (as of 2024)Ref
1APD3Includes AMP sequences, sources, classifications, targets, and antimicrobial spectrum. Offers tools for analysis, classification, and AMP design.https://aps.unmc.edu/AP/ (accessed on 22 April 2025)>3000[54]
2CAMPR3Includes both natural and synthetic AMP sequences. Supports predictions of antimicrobial activity and analysis of physicochemical properties.http://www.camp3.bicnirrh.res.in (accessed on 22 April 2025)>10,000[81]
3DBAASPIncludes AMP sequences, structures, and bioactivities. Offers tools for analyzing sequence–activity relationships, facilitating peptide optimization.https://dbaasp.org (accessed on 22 April 2025)>20,000[82]
4DRAMPIncludes detailed information on natural, synthetic, and modified AMPs. Provides data on peptide sequences, activity, and physicochemical properties.http://dramp.cpu-bioinfor.org/ (accessed on 22 April 2025)>30,000[83]
5YADAMPIncludes AMP sequences and detailed information on source species. Provides sequence search and target matching tools.http://yadamp.unisa.it/ (accessed on 22 April 2025)>10,000[84]
6SATPdbContains AMPs from various databases and allows searches for different peptide properties based on a query.http://crdd.osdd.net/raghava/satpdb/ (accessed on 22 April 2025)>8000[85]
7dbAMPAn integrated system for identifying AMPs and their functional types based on high-throughput transcriptomic and proteomic data.https://awi.cuhk.edu.cn/dbAMP/index.php (accessed on 22 April 2025)>10,000[86]
Table 2. Advancements in AMP-nanomaterial research could potentially be applied in agriculture.
Table 2. Advancements in AMP-nanomaterial research could potentially be applied in agriculture.
No.NanoparticleDescriptionRef
1Silver nanoparticlesIn vitro assays showed reduced AgNP cytotoxicity, enhanced antimicrobial activity, and improved stability in aqueous solutions.[109]
2CubosomesAMPs can be loaded into cubosomes with various formulations, and peptide loading efficiency depends on cubosome properties like lipid structure and curvature.[110]
3MicroemulsionsIn vitro assays evaluated a microemulsion with essential oils for encapsulating nisin and enhancing its antimicrobial activity on lettuce leaves.[111]
4Nanoparticle self-assembleIn planta assays showed a reduction in citrus canker lesion development, inhibition of biofilm formation, membrane damage, and altered cell membrane permeability.[112]
5Cu-Ag nanoparticles; multiwalled carbon nanotubesThe nanocomposites showed broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens, with glasshouse trials confirming their efficacy in protecting rice and tomato.[113]
Table 3. AMPs with protective effects against plant pathogens.
Table 3. AMPs with protective effects against plant pathogens.
No.NameSourceTargetMechanismApplication
1MaSAMPMicrocitrus australasicaCandidatus Liberibacter asiaticusAntimicrobial activity and immunity inductionSpray
2APP3-14Artificially designedCandidatus Liberibacter asiaticusAntimicrobial activity and immunity inductionInjection
3BP15Artificially designedStemphylium vesicariumAntimicrobial activitySpray
4pro-SmAMP2Stellaria mediaAlternaria and FusariumAntimicrobial activityTranformation
5LL-37HumanFusarium oxysporumAntimicrobial activity and immunity inductionTranformation
6Rs-AFPRaphanus sativusAlternaria longipesAntimicrobial activityTranformation
7DrsB1-CBDArtificially designedAlternaria, Fusarium, PythiumAntimicrobial activityTranformation
8AlfAFPMedicago sativaVerticillium dahliaeAntimicrobial activityTranformation
9BSD1Brassica campestrisPhytophthora parasiticaAntimicrobial activityTranformation
10Dm-AMP1Dahlia merckiiBotrytis cinereaAntimicrobial activityTranformation
11Pn-AMPPharbatis nilPhytophthora parasiticaAntimicrobial activityTranformation
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Sun, D.; Jia, Z.; Zhu, J.; Liu, J.; Chen, Y.; Xu, Z.; Ma, H. Antimicrobial Peptides and Their Potential Applications in Plant Protection. Agronomy 2025, 15, 1113. https://doi.org/10.3390/agronomy15051113

AMA Style

Sun D, Jia Z, Zhu J, Liu J, Chen Y, Xu Z, Ma H. Antimicrobial Peptides and Their Potential Applications in Plant Protection. Agronomy. 2025; 15(5):1113. https://doi.org/10.3390/agronomy15051113

Chicago/Turabian Style

Sun, Deming, Zhaohui Jia, Junjie Zhu, Jinhua Liu, Yichao Chen, Zhi Xu, and Haijie Ma. 2025. "Antimicrobial Peptides and Their Potential Applications in Plant Protection" Agronomy 15, no. 5: 1113. https://doi.org/10.3390/agronomy15051113

APA Style

Sun, D., Jia, Z., Zhu, J., Liu, J., Chen, Y., Xu, Z., & Ma, H. (2025). Antimicrobial Peptides and Their Potential Applications in Plant Protection. Agronomy, 15(5), 1113. https://doi.org/10.3390/agronomy15051113

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