Microbial- and Plant-Derived Bioactive Peptides and Their Applications against Foodborne Pathogens: Current Status and Future Prospects

Abstract

Bioactive peptides (BAPs) obtained from plants and microbes have been thoroughly explored and studied due to their prophylactic properties. The use of BAPs seems to be a promising substitute for several currently available antibiotics because of their antimicrobial properties against foodborne pathogens. BAPs have several other useful properties including antitumor, antihypertensive, antioxidant, antiobesity, and antidiabetic activities. Nowadays, scientists have attempted to recombinantly synthesize bioactive peptides to study their characteristics and potential uses, since BAPs are not found in large quantities in nature. Many pathogenic microorganisms including foodborne pathogens are becoming resistant to various antibiotics. To combat these pathogens, scientists are working to find novel, innovative, and safe antimicrobial agents. Plant- and microbe-based BAPs have demonstrated noteworthy antimicrobial activity against a wide range of pathogenic microorganisms, including foodborne pathogens. BAPs can kill pathogenic microorganisms by disrupting membrane integrity, inhibiting DNA and RNA synthesis, preventing protein synthesis, blocking protein activity, or interacting with certain intracellular targets. In addition, the positive effect of BAP consumption extends to gut microbiota modulation and affects the equilibrium of reactive oxygen species in the gut. This article discusses recombinant BAPs, BAPs generated from plants and microbes, and their antimicrobial applications and modes of action for controlling foodborne pathogens.

1. Introduction

Bioactive peptides have been thoroughly researched for their health advantages and possible applications as nutraceuticals and functional food ingredients [1]. Emerging antibiotic resistance (ABR) related to foodborne illnesses harms both human and animal populations as well as the economy and human health suffers greatly from bacterial resistance which prompts food to deteriorate and causes health problems. Finding antibiotic substitutes that can reduce health risks and the consequences of numerous foodborne illnesses is now vital [2]. If BAPs are employed as food additives or preventative measures, they exhibit potential as safe food supplements with a variety of health benefits and BAPs are less likely than antibiotics to cause bacteria to evolve resistance [3].

BAPs are often embedded in the structure of large proteins and are cleaved to become active. They consist of short amino acid (aa) sequences (2–20 aa) that provide beneficial health facilities, such as, in the form of controlling foodborne pathogens [4]. They can be derived from microbes, plants, and animal tissues. In addition, food processing (cooking, fermentation, and ripening) or microbial enzyme maturation may produce BAPs. Products including milk, cheese, yogurt, sausage, eggs, soybeans, soy milk, chia, rice bran, peas, flaxseed, mushrooms, and cauliflower are considered richer sources of BAPs [5]. Many classes of BAPs are currently available for purchase chemically or recombinantly [6].

There are a variety of plant-derived BAPs such as puroindolines, lipid transfer proteins, thionins (α/β, γ), glycine-rich peptides, hevein-like peptides, plant defensins, and knottin-like peptides. Numerous classes of stems, roots, seeds, flowers, and leaves have all been found to contain BAPs and they show activity against both phytopathogens and bacteria that are harmful to humans [7]. Microbes also produce a large variety of biologically active peptides such as pediocins, nisin, enterocin, propionicin, gramicidin, endolysins, and apicidin. These peptides are derived from viruses, bacteria, and fungi. They protect organisms from invasive bacteria, viruses, protozoa, and fungi by disrupting the membrane or metabolic processes [8].

Peptides can regulate a number of vital physiological functions such as hormones. Their positive health impacts include cardiovascular disease reduction, immunomodulatory, antihypertensive effects, mineral binding, chelating action, and anticoagulant, antioxidative, and antimicrobial properties. Besides, they are in charge of the flavor of the food as well as preventing the activity of enzymes that cause diseases to develop [8]. Some BAPs through their antimicrobial activity protect mammals from various foodborne pathogens as well as their direct impact on the shelf life of prepared foods has made them highly desirable in this industry [9]. These peptides can change the biological processes of pathogens, such as the growth of cells and the formation of cell membranes. They are thought to work by opening up channels or pores in bacterial membranes, which prevent anabolic processes, and alter gene expression and signal transmission while encouraging angiogenesis [10]. Another immunomodulatory result, that may halt the spread of foodborne illnesses caused by the foodborne pathogen, Listeria monocytogenes can lead to severe listeriosis and develop resistance to antibiotics [11]. Therefore, as an antimicrobial peptide, BAP can kill pathogens through a variety of actions such as interrupting membrane integrity, hindering DNA and RNA synthesis, preventing protein synthesis, and acting on particular intracellular targets [12, 13]. Besides, the positive effect of BAP by consuming it also includes gut microbiota regulation. Recent research has linked the prevention and treatment of neurodegenerative illnesses such as Parkinson's disease, Alzheimer's disease, and dementia to gut microbiome modifications supported by BAPs [14, 15].

Food safety and human health are seriously compromised by foodborne pathogens. They are responsible for various life-threatening diseases in humans. Moreover, a large number of these foodborne bacteria are developing antibiotic resistance on a daily basis [11]. Therefore, it is essential to develop safe and effective antimicrobial agents to control these foodborne pathogens (e.g., viruses, bacteria, and parasites) for food safety as well as to protect human health. Bioactive antimicrobial peptides could be a good option for the development of novel antimicrobial agents against foodborne pathogenic microorganisms such as Escherichia coli, Salmonella, Listeria, Cyclospora, Campylobacter, and Shigella. The naturally derived BAPs possess significant antiviral activity against the hepatitis virus along with other viruses as these BAPs can inhibit viral entry into the host cells and interfere with host-specific interactions. From this perspective, this review highlights currently known plant- and microbes-derived bioactive BAPs as well as recombinant BAPs with their mechanisms of action for controlling foodborne pathogens and their prospects.

2. BAPs from Different Sources

2.1. Plant-Derived BAPs

Plants produce a large variety of biologically active peptides such as thionins (α/β, γ), puroindolines, lipid transfer proteins, plant defensins, glycine-rich peptides, hevein-like peptides, knottin-like peptides, and homologs of MBP-1, which work against bacterial and fungal pathogens (Table 1). There are five types of thionins: grain endosperms that contain purothionins, which are type I thionins; α-hordothionin and β-hordothionin are type II thionins that are found in Pyrularia pubera leaves and nuts; ligatoxin A and viscotoxins are examples of type III thionins; and crambin and hellothionin D peptides belong to groups IV and V, respectively [7, 13, 16]. Plant defensins are small, cysteine-rich, cationic antimicrobial peptides containing conserved 3D structures comprising one α-helix and three antiparallel β-strands. γ-Hordothionin is a member of plant defensins and Ah-AMP1, Ct-AMP1, Rs-AFP1, PhD1, and Hs-AFp1 are examples of plant defensins [7, 45]. Most plant defensins fall into one of the three categories based on the quantity and location of cysteine residues inside the molecules: hevein-type, knottin-type, and thionin-type [50].

Table 1.

Plant-derived bioactive peptides and their potential antimicrobial applications.

Name of the peptide	Plant source	Target pathogen	Mode of action	References
Thionins	Wheat, barley, oats, rice, rye, mistletoe, oil nut, and Abyssinian cabbage	Bacteria	Pore formation, ion channel formation, cell membrane disruption, and protein synthesis inhibition	[13]
		Gram-positive or Gram-negative bacteria such as Pseudomonas, Xanthomonas, Agrobacterium, Erwinia, and Corynebacterium
Purothionin	Wheat	Bacteria	Interfere with DNA synthesis by inhibiting the activity of the enzyme ribonucleotide reductase, and also inhibit the activity of β-glucuronidase	[13, 16]
		Pseudomonas solanacearum, Xanthomonas phaseoli, Xanthomonas campestris, Erwinia amylovora, Corynebacterium flaccumfaciens, Corynebacterium michiganense, Corynebacterium poinsettiae, Corynebacterium sepedonicum, and Corynebacterium fascians
WAMP_1a and WAMP_1b	Seeds of T. kiharae	Fungi	Growth inhibition and induced destruction	[17, 18]
		Fusarium solani, Fusarium oxysporum, and Helminthosporium sativum
		Bacteria
		Gram-positive
		Clavibacter michiganense, Gram-negative
		Pseudomonas syringae
		Erwinia carotovora
Lc-Def	Lentil	Fungi	Electrostatic interaction with anionic lipid components of fungal membranes	[18]
		Aspergillus niger, Aspergillus versicolor, Botrytis cinerea, Fusarium culmorum, Fusarium solani, and Neurospora crassa
AFP-J	Potato tuber (Solanum tuberosum cv. L Jopung)	Fungi	Inhibit serine protease activity	[12, 19]
		Trichosporon beigelii, S. cerevisiae, and Candida albicans
		Bacteria
		Staphylococcus aureus, Listeria monocytogenes, and Escherichia coli
Potide-G	Potato tubers	Bacteria	Suppressed proteolytic activity of trypsin, chymotrypsin, and papain	[12]
		Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Clavibacter michiganensis subsp. michiganense
		Fungi
		C. albicans and R. solani
		Virus Potato virus Y
PKPI and PPI-I	Potato sprout	Fungi	Inhibit fungal protease, spore germination, hyphal elongation, and the development of necrotic lesions	[12]
		Botrytis cinerea
Potato pseudothionin solanum tuberosum 1 (Pth-St1)	Potato tubers	Bacteria	Bind to the membrane receptor, chelation of Ca2+, and consequently, pores are being formed	[12, 20, 21]
		Clavibacter michiganensis and Pseudomonas solanacearum
		Fungi
		F. solani
PKI1 and PPI3B2	Potato	Fungi	Fungal proteases affect spore germination, hyphal elongation, and development of necrotic lesions	[22]
		Botrytis cinerea
PLPKI	Potato	Phytophthora infestans and Rhizoctonia solani	Inhibited the activity of extracellular proteases	[23]
PSPI-21 and PKSI	Potato tubers	Fungi	Serine proteinases inhibitor (affect the growth of oomycete mycelium and fungal mycelium) induces complete destruction of oomycete zoospores and partial destruction of fungal macroconidia	[24]
		Phytophthora infestans and Fusarium culmorum
Snakins (SN1 and SN2)	Potato	Bacteria	Rapid aggregation of both Gram-positive and Gram-negative bacteria	[12, 25]
		C. michiganensis subsp. Sepedonicus, Ralstonia solanacearum, and R. meliloti
		Fungi
		B. cinerea, Fusarium oxysporum f. sp. Conglutinans, F. solani, Bipolaris maydis, Aspergillus flavus, and Colletotrichum graminicola
2S albumin-like protease inhibitor	Barley seeds	Fungi	Permeabilize fungal membranes	[19, 26]
		Alternaria brassicicola, Botrytis cinerea, Fusarium culmorum, Fusarium oxysporum f.sp. lycopersici, Pyricularia oryzae, and Verticillium dahlia
Trypsin and chymotrypsin inhibitors	Cabbage leaves	Fungi	Blocked the synthesis of chitin in the cell wall, and weakened the fungal hyphae, thus inducing the leakage of intracellular contents from susceptible fungal species	[19, 27]
		Botrytis cinerea and Fusarium solani
ZmESR-6	Kernels of maize	Bacteria	Inhibit protein synthesis and block ion channels	[28, 29]
		Clavibacter Michiganensis, Xanthomonas campestris, and Rhizobium meliloti
		Fungi
		Fusarium oxysporum f.sp. Conglutinans, Fusarium oxysporum f.sp.lycopersici, and Plectosphaerella cucumerina
Fabatin	Broad bean	Bacteria	Insertion into the plasma membranes of bacterial cells, leading to depolarization of the membrane and cell lysis	[29–31]
		Escherichia coli, Enterococcus hirae, and Pseudomonas aeruginosa
VaD1	Azuki bean	Bacteria	Inhibit protein synthesis	[29, 32]
		Staphylococcus epidermis, Xanthomonas campestris pv. vesicatoria, and Salmonella typhimurium
		Fungi
		Fusarium oxysporum, Fusarium oxysporum, and Trichophyton rubrum
So-D2 and So-D7	Spinach	Bacteria	Damage the cell wall via repression of gene expression or via restricting bacterial replication, causing cell lysis	[29, 33]
		Clavibacter sepedonicus and Ralstonia solanacearum
Tu-AMP1 and Tu-AMP2	Tulipa gesneriana	Bacteria	Positively charged proteins interact with negatively charged membrane phospholipids, following a membrane permeability modification	[21, 29]
		Erwinia carotovora subsp. Carotovora, A. tumefaciens, Clavibacter michiganensis, and Curtobacterium flaccumfaciens pv. oortii
Pp-AMP 1 and Pp- AMP 2	Japanese bamboo shoots	Bacteria	Binds to specific phospholipids and cause the exposure of toxicity, resulting in cationic imbalance	[21]
		E. carotovora, A. radiobacter, A. rhizogenes, C. michiganensis, and C. flaccumfaciens
MtDef5	Medicago truncatula	Bacteria	Permeabilizes the plasma membrane, translocates into the cells of this bacterial pathogen and binds to DNA, membrane permeabilization, and fungal growth arrest	[29, 34]
		Xanthomonas campestris pv. Campestris
		Fungi
		Fusarium graminearum and Neurospora crassa
Tad1	Winter wheat	Pseudomonas cichorii	Unknown	[29]
OsDef7 and OsDef8	Rice Oryza sativa	Bacteria	Interact with the negatively charged phospholipids on the bacterial membrane surface and fungal membrane destabilization	[29, 35]
		Xanthomonas oryzae, pv. oryzae, X. oryzae pv. oryzicola, Erwinia carotovora subsp. atroseptica, Pseudomonas aeruginosa, and Dickeya dadantii
		Fungi
		Helminthosporium oryzae and Fusarium oxysporum f.sp. cubense
PvD1	Seeds	Fungi	Oxidative damage related to the induction of ROS and NO production, cytoplasmic fragmentation, formation of multiple cytoplasmic vacuoles, and membrane permeabilization in the cells of this organism	[36, 37]
		C. albicans
		Protozoa
		Leishmania amazonensis
Limenin	Phaseolus limensis	Bacteria	Membrane collapse by interacting with lipid molecules on the bacterial cell surface, inhibiting the translation of fungi. HIV-1 reverse transcriptase inhibition	[29, 38, 39]
		Mycobacterium phlei, Proteus vulgaris, Bacillus megaterium, and Bacillus subtilis
		Fungi
		Botrytis cinerea, Fusarium oxysporum, and Mycosphaerella arachidicola
		Virus
		HIV-1
Ct-AMP1	Clitoria ternatea	Fungi	Cause a reduction in hyphal thickness and an apparent collapse of the plasma membrane leading to an apparent fragmentation of the cytoplasm	[29, 40]
		Botrytis cinerea, Cladosporium sphaerospermum, Fusarium culmorum Leptosphaeria maculans, Penicillium digitatum, Trichoderma viride, Septoria tritici, and Verticillium albo-atrum
J1-1	Capsicum annuum	Bacteria	Binds with phosphoinositides (PIs) and PA	[29]
		Pseudomonas aeruginosa
		Fungi
		Fusarium oxysporum and Botrytis cinerea
MsDef1	M. sativa	Fungi	Ion channel blocking and hyperbranching	[41]
		F. graminearum
HaDEF1	Sunflower	Fungi	Membrane permeabilization and apoptosis	[41]
		O. Cumana, O. Ramosa, S. cerevisiae, and A. brassicicola
Fa-AMP1 and Fa-AMP2	Buckwheat seeds	Bacteria	Disruption of microbial membranes and phospholipid liposomes, an interaction with a specific receptor as an ion channel or a sphingolipid	[21, 29]
		Erwinia carotovora subsp. carotovora, Agrobacterium tumefaciens, Clavibacter michiganensis, and Curtobacterium flaccumfaciens pv. oortii
		Fungi
		Fusarium oxysporum and Geotrichum candidum
α-Hordothionins	Barley	Bacteria	Interacting electrically with fungal lipid bilayer and linking to the membrane surface, leading to permeabilization and disruption of the membrane organization	[21, 42]
		Clavibacter michiganensis subsp. michiganensis and Xanthomonas campestris pv. vesicatoria
Pa-AMP-1	Pokeweed seeds	Fungi	Interact with the phospholipids of cell membranes, resulting in the inhibition of fungal growth	[42, 43]
		Alternaria panax and Fusarium sp., Rhizoctonia solani
Cp-thionin II (γ-thionins)	Cowpea seeds	Bacteria	Insertion into the plasma membranes of bacterial cells, leading to depolarization of the membrane, cell lysis, and permeabilization of the hyphae, leading to leakage and granulation of the plasma membrane, and increased generation of reactive oxygen species (ROS) causes fungal growth inhibition	[29, 30, 44]
		Pseudomonas syringae, Staphylococcus aureus, and Escherichia coli
		Fungi
		F. culmorum
Dm-AMP1	Dahlia merckii	Fungi	Causes a reduction in hyphal thickness and an apparent collapse of the plasma membrane leading to an apparent fragmentation of the cytoplasm	[29, 40]
		Botrytis cinerea, Cladosporium sphaerospermum, Fusarium culmorum Leptosphaeria maculans, Penicillium digitatum Trichoderma viride, Septoria tritici Verticillium albo-atrum
Hs-AFP1	Heuchera sanguinea	Fungi	Causes germ tubes and hyphae to swell and form multiple hyphal buds, membrane permeabilization, ROS, and apoptosis	[40, 41]
		Botrytis cinerea, Cladosporium sphaerospermum, Fusarium culmorum, Leptosphaeria maculans, C. albicans, C. krusei, A.flavus, Penicillium digitatum, Trichoderma viride, Septoria tritiei, and Verticillium albo-atrum
Rs-AFP2	Radishes	Fungi	Causes germ tubes and hyphae to swell and form multiple hyphal buds, membrane permeabilization, ROS, apoptosis, inhibit cell growth, and ion flux	[40, 41]
		Botrytis cinerea Cladosporium sphaerospermum, Fusarium culmorum Neurospora crassa Leptosphaeria maculans, Penicillium digitatum Trichoderma viride Septoria tritici Verticillium albo-atrum
Hc-AFP	Heliophila coronopifolia	Fungi	Hyperbranching, fungal tip swelling, increased granulation of hyphae and spores, as well as hyphal and spore, and membrane permeabilization disruption	[41]
		Botrytis cinerea
		Fusarium solani
Ah-AMP1	Horse chestnut	Fungi	Reducing hyphal thickness and collapse of the plasma membrane causes an apparent fragmentation of the cytoplasm	[29, 40]
		Botrytis cinerea, Cladosporium sphaerospermum, Fusarium culmorum, Leptosphaeria maculans, Penicillium digitatum Trichoderma viride Septoria tritici, and Verticillium albo-atrum
NaD1 γ-thionin-like protein	Nicotiana alata	Fungi	Interacting with the cell wall causes the destruction of internal membrane integrity by membrane permeabilization and targets internal organelles by inducing the development of reactive oxygen species (ROS) and fungal cell death	[37, 41, 45]
		Leptosphaeria maculans, V. dahlia, Thielaviopsis basicola, Aspergillus nidulans, C. albicans, C. neoformans, C. gattii, and Fusarium oxysporum
BCP-2 alpha thionin	Barley grain	Fungi	Bind to glucosylceramides and sphingolipids, leading to fungal cell lysis	[21, 44, 46]
		Botrytis cinerea
		Trichoderma viride
Mo-CBP2 (chitin-binding protein)	Seeds	Fungi	Increased the cell membrane permeabilization and produce reactive oxygen species, have DNase activity	[47]
		Candida albicans, C. parapsilosis, C. krusei, and C. tropicalis
Mo-CBP3	Seeds	Fungi	Inhibited spore germination and mycelial growth induced the production of ROS and caused disorganization of both the cytoplasm and the plasma membrane leading to cell death	[48]
		Fusarium solani, F. oxysporum, Colletotrichum musae, and C. gloeosporioides
Cy-AMP1	Cycad seeds	Fungi	Bind to chitin of fungus surface	[49, 50]
		F. oxysporum
		G. candidum
Lunatusin	Chinese lima bean	Bacteria	Causes membrane collapse by interacting with lipid molecules on the bacterial cell surface, inhibits mycelial growth of fungi, and inhibits HIV-1 reverse transcriptase protein-protein inhibition	[16, 38, 49]
		Bacillus megaterium, B. subtilis, P. vulgaris, and Mycobacterium phlei
		Fungi
		Fusarium oxysporum, Mycosphaerella arachidicola, and Botrytis cinerea
		Virus
		HIV-1
Vulgarinin	Haricot beans	Bacteria	Cell membrane disruption, growth inhibition, and death of bacteria, interaction with phosphorylinositol containing sphingolipids or glycosylceramides cause subsequent fungal cell death, and inhibit HIV-1 reverse transcriptase, protease, and integrase	[16, 38, 51]
		Mycobacterium phlei, Bacillus megaterium, B. subtilis, P. vulgaris
		Fungi
		Botrytis cinerea, Fusarium oxysporum, Physalospora piricola, and Mycosphaerella arachidicola
		Virus
		HIV-1
Hispidalin	Benincasa hispida	Bacteria	Amphipathicity and cationic charge of peptide facilitates the peptide attachment and insertion into the bacterial membrane to create transmembrane pores resulting in membrane permeabilization. Fungal hyphae growth inhibition	[16, 52]
		S. enterica, S. aureus, E. coli, and P. aeruginosa
		Fungi
		A. flavus, F. solani, C. geniculate, and P. chrysogenum
(Cg24-I)	Carica candamarcensis, C. papaya, and Cryptostegia grandiflora	Fungi	Inhibition of mycelia growth and spore germination	[16, 53]
		F. solani, R. solani, and F. oxysporum
CpLP cysteine-like proteases	Calotropis procera	Fungi	Fungal growth inhibition, production of ROS lead to oxidative stress, loss of cell function, and ultimately cell death by apoptosis or necrosis	[54]
		Colletotrichum gloeosporioides, Fusarium oxysporum, Fusarium solani, Rhizoctonia solani, Neurospora sp., and Aspergillus Niger
IbAMP1 plant defensin	Seeds	Bacteria	Increase permeability to the cell membrane, permitting efflux of ATP and interfering with intracellular molecular processes (DNA, RNA, and protein synthesis)	[55, 56]
		E. coli O157: H7 and Staphylococcus aureus
WAMPs (hevein-like AMPs)	Wheat	Fungi	Cell wall/membrane disruption, the peptide penetrates through the fungal cell walls and interferes with fungal growth by binding or cross-linking the newly-synthesized chitin chains, penetrating into the fungal hyphae and localized at the septum and hyphal tips, resulting in hyphal tip burst and leakage of the cytoplasmic constituents. Active against fungal metalloproteases	[57, 58]
		C. cucumerinum, A. alternata F. oxysporum, and B. sorokiniana
AX (cysteine-rich proteins)	Sugar beet leaves	Fungi	Reduction of hyphal growth	[59]
		C. beticola
Ay-AMP	Amaranthus hypochondriacus seeds	Fungi	Degrades chitin of the fungal cell walls and accumulates at septa and hyphal tips by the union to the fungus cell wall chitin, inhibiting the growth	[60]
		Candida albicans, Trichoderma sp., Fusarium solani, Penicillium chrysogenum, Geotrichum candidum, Aspergillus candidus, Aspergillus. ochraceus, and Alternaria alternata
Pn-AMPs (hevein-type)	Seeds of morning glory	Fungi	Penetrated very rapidly into fungal hyphae and localized at septum and hyphal tips of fungi, which caused the burst of hyphal tips. The burst of hyphae resulted in disruption of the fungal membrane and leakage of the cytoplasmic materials	[61]
		Botrytis cinerea, Phytophthora parasitica, Fusarium oxysporum, Rhizoctonia solani, and Saccharomyces cerevisiae
GAFP (hevein-type)	Ginkgo biloba	Fungi	Burst of hyphal tips increased hyphal membrane permeabilization	[7]
		Fusarium graminearum, Fusarium moniliforme, Pellicularia sasakii Ito, and Alternaria alternata
Ns-D1 and Ns-D2	Nigella sativa seeds	Fungi	Inhibited hyphal growth	[7, 62]
		Aspergillus niger, Fusarium oxysporum, Fusarium graminearum, Fusarium culmorum, Bipolaris sorokiniana, and Botrytis cinerea
PINA and PINB (puroindoline)	Wheat	Fungi	Interactions with cellular membranes and ion channel formation in the membranes	[7]
		Alternaria brassicicola, Ascochyta pisi, Botrytis cinerea, Verticillium dahliae, Fusarium culmorum, and Cochliobolus heterostrophus
Ha-AP10 (lipid transfer proteins)	Sunflower seeds (Helianthus annuus)	Fungi	Membrane permeabilization by electrostatic interaction with anionic membrane phospholipids induces liposome leakage and permeabilization of fungal spores	[55, 63]
		Fusarium solani
WjAMP1 (hevein-like AMPs)	Leaves of Wasabia japonica L.	Bacteria	Peptide binding to the membrane can activate several pathways that will cause cell death	[7, 38, 64]
		Escherichia coli
		Agrobacterium tumefaciens
		Pseudomonas cichorii
		P. plantarii
		P. glumae
		Fungi	Inhibit spore germination and hyphal growth, interaction with fungal membrane lipids resulting in the formation of membrane pores, and leakage of cytoplasmic materials
		Botrytis cinerea
		Fusarium solani
		Magnaporthe grisea
		Alternaria alternata
LTP protein (lipid transfer proteins)	Wheat	Fungi	Fungal membranes form a pore resulting in an efflux of intracellular ions culminating in cell death	[7]
		Rhizoctonia solani
		Curvularia lunata
		Alternaria sp.
		Bipolaris oryzae
		Cylindrocladium
		Scoparium
		Botrytis cinerea
		Sarocladium oryzae
Kalata B (cyclotide)	Oldenlandia affinis	Bacteria	Induces leakage of contents from phospholipid vesicles and forms large pores in lipid bilayers, has lytic ability causing membrane leakage of helminth, and inhibits the development of nematode larvae and motility of adult worms	[7, 65]
		Staphylococcus aureus
		E. coli
		Nematode
		Haemonchus contortus
		Trichostrongylus colubriformis
Shepherins (glycine- and histidine-rich peptides)	Capsella bursa-pastoris	Bacteria	Insertion into the membrane, triggering disruption of lipid bilayer physical integrity, membrane thinning/formation of transient pores, and destabilization of internal membranes, leading to disruption of the endosome	[66, 67]
		Erwinia herbicola, Escherichia coli, and Pseudomonas putida
		Fungi
		S. cerevisiae
		C. albicans
		Cryptococcus neoformans

2.2. Microbe-Derived BAPs

Microbe-derived BAPs are found in viruses, bacteria, and fungi. These peptides are classified based on their sources, structural characteristics, amino-acid-rich content, and activities. Viral BAPs are phage proteins containing virion-associated peptidoglycan hydrolases, depolymerases, lysins, and holins called enzybiotics. Phage-tail complexes and phage-encoded lytic factors are two types of phage BAPs. Bacterial BAPs are produced by both Gram-positive and Gram-negative bacteria. Gram-positive bacterial BAPs are classified as ribosomally-produced BAPs known as bacteriocin and nonribosomally or enzymatically-produced BAPs [8]. There are two types of bacteriocins: lantibiotics and nonlantibiotics (lantibiotics contain unnatural amino acid lanthionine) [68]. Gram-negative bacterial bacteriocins are grouped into colicins, microcins, colicin-like bacteriocins, and phage-tail-like bacteriocins. Defensins and peptaibol are the two types of fungal BAPs. Peptaibol contains the name in combination with peptide, α-aminoisobutyrate, and amino alcohols. Microbe-derived BAPs and their potential antimicrobial applications are shown in Table 2.

Table 2.

Microbe-derived bioactive peptides and their potential antimicrobial applications.

Name of the peptide	Microbial source	Target pathogen	Mode of action	References
Pediocins	Pediococcus spp.	Bacteria	Disrupt proton motive force, formation of pores in the cytoplasmic membrane, and cell membrane dysfunction	[69]
		Listeria monocytogenes
Nisin	Lactococcus lactis	Bacteria	Pore formation and the inhibition of cell wall biosynthesis	[70–72]
		Listeria monocytogenes
		Streptococcus aureus
		Spore-forming Bacillus Clostridium species
Lacticin 3147	Lactococcus lactis	Bacteria	Cell wall disruption and pore formation	[70]
		Staphylococcus aureus
		Enterococcus faecalis
		Pneumococcus
		Propionibacterium acnes, Streptococcus mutans, and Listeria monocytogenes
		Bacillus cereus
Enterocin A	Enterococcus faecium	Bacteria	Interacts with cell wall and cell receptor, membrane permeabilization causes the leakage, and interferes in DNA replication and mRNA synthesis and transcription	[72, 73]
		L. monocytogenes
		Staphylococcus aureus and Salmonella enterica
Propionicin	P. thoenii, P. jensenii, and P. freudenreichii	Bacteria	Unknown	[74, 75]
		Helicobacter pylori
		Listeria monocytogenes
		Corynebacterium spp.
		Vibrio parahaemolyticus
		Yersinia enterocolitica
		Pseudomonas spp.,
		Saccharomyces spp.
		Aspergillus spp.
		Fungi
		Aspergillus wentii and Apiotrichum curvatum
		Fusarium tricinctum and Phialophora gregata
		Candida, Saccharomyces, and Scopulariopsis genera
Lynronne	Rumen microbiome	Bacteria	Membrane permeabilization pore formation and lysis	[76, 77]
		Staphylococcus aureus
		Acinetobacter baumannii
		P. aeruginosa
Gramicidin S	Aneurinibacillus migulanus	Bacteria	Binding of peptides to Gram-negative LPS and their ability to disrupt Gram-negative cell membranes, accumulation of bacterial membrane phospholipids, and pore formation in the cell membrane	[78, 79]
		E. coli
		Klebsiella pneumoniae and Pseudomonas aeruginosa
		Acinetobacter baumannii Staphylococcus aureus
		Enterococcus faecium
Gramicidin A	Bacillus brevis	Bacteria	Membrane permeabilization, interruption of internal molecular function (DNA and protein functions), formation of hydroxyl free radicals, and the imbalance of NADH metabolism	[80, 81]
		Staphylococcus aureus
Gramicidin A (1)	Bacillus brevis	Bacteria	Disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer	[82]
		S. pyogenes and S. pneumoniae
		Enterococcus faecalis
		Streptococcus agalactiae
Endolysins (phage-derived AMP)	Bacteriophages of A. baumannii	Bacteria	Cause hydrolysis of bacterial cell wall	[83]
		Acinetobacter baumannii
		Fungi
		Aspergillus fumigatus
		Candida albicans
Tyrocidines	Bacillus aneurinolyticus	Bacteria	Binds to bacterial membranes and disrupts structural integrity, resulting in bacterial cell death, disruption of the asexual cycle of the parasite and inhibit the respiration of parasitized red cells	[84–87]
		B. Subtilis
		C. albicans
		Parasite
		Caenorhabditis elegans
		Plamodium gallinaceum
Valinomycin	Streptomyces cavourensis, S. fulvissimus, S. roseochromogenes, and S. griseus	Bacteria	Degradation of glycolytic ATP affects respiration and disrupts the K+ ion gradient across the cell membrane, and the unbalanced distribution of ions in the bacterium causes cell death and fungal cell wall and cell membrane permeabilization	[88–90]
		Streptococcus faecalis and Micrococcus lysodeikticus
		Staphylococcus aureus
		Fungi
		Candida albicans
		Cryptococcus albidus
Aureobasidin A 1 (cyclodepsipeptides)	Aureobasidium pullulans R106	Fungi	Affect spore germination rate, germination initiation, polarized growth of germ tube, and elongation rate; inhibit inositolphosphoryl-ceramide (IPC) synthase; inhibition of sphingolipid biosynthesis resulting in loss of intracellular structure and vacuolization; and membrane trafficking which disturbed cell proliferation of the parasite	[91]
		Penicillium digitatum
		P. italicum, P. expansum, Botrytis cinerea, and Monilinia fructicola
		C. albicans, S. cerevisiae, and C. neoformans
		A. fumigates, Schizosaccharomyces pombe, and A. nidulans
		A. Niger and A. oryzae
		Parasite
		Toxoplasma gondii
		Leishmania amazonensis
Colistin (polymyxin E)	Paenibacillus polymyxa	Bacteria	Increase the permeability of the bacterial membrane, leading to leakage of the cytoplasmic content and causing cell death, and bind to lipid portion A and neutralize and inhibit vital respiratory enzymes	[92]
		E. coli and A. baumannii
		P. aeruginosa and Stenotrophomonas maltophilia
		Enterobacter spp.
		Klebsiella spp.
		Citrobacter spp.
		Salmonella spp., and Shigella spp.
Omphalitis	Omphalotus olearius	Nematodes	Unknown	[93]
		Meloidogyne incognita and Caenorhabditis elegans
Daptomycin	Streptomyces roseosporus	Bacteria staphylococci and enterococci	Bacterial cell membrane, causing rapid membrane depolarization and a potassium ion efflux, followed by the arrest of DNA, RNA, and protein synthesis, resulting in bacterial cell death	[94, 95]
Pargamicin A	Amycolatopsis sp.	Bacteria	Disruption of the membrane potential, leading to loss of the membrane function	[94, 95]
		S. aureus and E. faecalis
Nocardithiocin	Nocardia pseudobrasiliensis	Bacteria	Cell membrane or cell wall permeability	[94, 96]
		Mycobacterium
		Gordonia species
		M. tuberculosis
Xylapeptide	Xylaria sp.	Bacteria	Unknown	[94]
		Bacillus subtilis
		B. cereus, B. megaterium, and Micrococcus luteus
		S. aureus and Shigella castellani
		Fungus
		C. albicans
Lugdunin	Staphylococcus lugdunensis	Bacteria	Impairment of membrane integrity or ion transport and proton leakage in synthetic, protein-free membrane vesicles	[94, 97, 98]
		Staphylococcus aureus and vancomycin-resistant Enterococcus
Venturamide	Oscillatoria sp.	Parasite	Unknown	[94]
		P. falciparum
Xenoamicin A	Xenorhabdus doucetiae and Xenorhabdus mauleonii	Parasite	Interacts with the cytoplasmic membrane	[94, 99]
		P. falciparum
		T. brucei rhodesiense
Szentiamide	Xenorhabdus szentirmaii	Parasite	Interacts with the cytoplasmic membrane	[99]
		Plasmodium falciparum
		Trypanosoma cruzi
		Bacteria
		M. luteus
Apicidin	Fusarium semitectum	Parasite	Inhibit histone deacetylase of parasite	[100, 101]
		Plasmodium falciparum and T. gondii
		Plasmodium berghei
Thiostrepton	Streptomyces azureus and Streptomyces laurentii	Parasite	Inhibition of protein synthesis by proteasome β subunits and inhibition of mRNA translation	[100]
		Plasmodium berghei
Amphomycin	Streptomyces canus	Parasite	Inhibits the biosynthesis of the glycolipid precursor of glycosylphosphatidylinositol (GPI) protein by which the variant surface glycoproteins (VSGs) are anchored in the membrane of the parasites	[100]
		Trypanosoma brucei
		T. b. gambiense
		T. b. rhodesiense
Leucinostatins (A and B) and alamethicin	Paecilomyces spp	Parasite	Pore formation in the membranes and interruption of cellular homeostasis, resulting in the death of the parasite	[100]
		Trypanosoma brucei
		T. b. brucei and T. b. rhodesiense
Haloduracin (lantibiotic)	Bacillus halodurans	Bacteria	Pore formation, cell membrane attack, and the inhibition of cell wall synthesis	[102]
		B. anthracis
		Vancomycin-resistant Enterococcus faecium, Bacillus cereus, and methicillin-resistant
		Staphylococcus aureus
Albicidin	Xanthomonas albilineans	Bacteria	Inhibit DNA replication, transcription, supercoiling, gene regulation, and catalytic DNA cleavage-religation cycle of the GyrA subunit	[103, 104]
		Enterobacter aerogenes
		Escherichia coli
		Haemophilus influenza
		Klebsiella pneumonia
		Shigella sonnei and Staphylococcus aureus
Griselimycin	Streptomyces griseus	Bacteria	Inhibit nucleic acid biosynthesis by sliding clamp of DNA polymerase III	[104, 105]
		Mycobacterium tuberculosis
Colicin E	Escherichia coli	Bacteria	Inhibit nucleic acid biosynthesis by cleaving the targeted cell's DNA or tRNA and digests the peptidoglycan precursors, leading to cell death pore formation in the inner membrane and degrade the internal molecular components	[71, 104, 106, 107]
		Shiga-toxin-producing E. coli
		Enteroinvasive
		E. coli and Shigella
		Enterobacter
		Klebsiella and Morganella
		Salmonella, Shigella, and Yersinia
Dudawalamides	Moorea producens	Parasite	Unknown	[94]
		P. falciparum, Trypanosoma cruzi, and Leishmania donovani
Ambobactin	Streptomyces ambofaciens	Bacteria	Target cytoplasmic membrane	[94, 108]
		Bacillus subtilis
		Escherichia coli
		Erwinia carotovora
		Pseudomonas syringae
		Fungi
		Ralstonia solanacearum and Xanthomonas oryzae
Teixobactin	Eleftheria terrae	Bacteria	Inhibits bacterial cell wall synthesis by binding to the precursor of peptidoglycan and teichoic acid	[94]
		S. aureus
		Streptococcus pneumonia, M. tuberculosis, Clostridium difficile, and Bacillus anthracis
Maribasins	Bacillus marinus	Fungi	Unknown	[109]
		Alternaria solani, Fusarium oxysporum, Rhizoctonia solani, and Verticillium albo-atrum
Clavariopsins	Clavariopsin aquatica	Fungi	Inhibit the synthesis of fungal cell walls	[91]
		C. albicans, Aspergillus fumigatus, and A. niger
Anidulafungin	Aspergillus oryzae	Fungi	Inhibition on β-(1,3)-glucan synthase	[109]
		Candida
GE81112	Streptomyces sp.	Bacteria	Inhibit bacterial protein synthesis machinery	[110]
		S. pneumoniae, E. faecalis, E. coli and B. subtilis, and S. pyogenes
Carmaphycin B	Symploca sp.	Parasite	Targets Plasmodium proteasome	[96]
		Plasmodium falciparum
Kakadumycin A	Streptomyces sp.	Bacteria	Binding to DNA prevents RNA synthesis	[111]
		Bacillus anthracis
		Enterococcus faecium, Staphylococcus simulans, and Staphylococcus aureus
		S. pneumonia
		Listeria monocytogenes
		Parasite
		Plasmodium falciparum
Fengycins	Bacillus subtilis	Fungi	Disrupt the mitochondrial membrane potential, production of reactive oxygen species, and chromatin condensation in fungal hyphal cells resulting in hyphal cell death	[112]
		Magnaporthe grisea
		Aspergillus niger
		Mucor rouxii
		Rhizopus stolonifer
		Gibberella zeae and Fusarium graminearum
		Sclerotinia sclerotiorum

2.3. Recombinant BAPs

Once the peptide sequence is revealed, it can be synthesized chemically or by utilizing recombinant DNA technologies. Hydrolysis by enzymes is a simple production process, but it takes time and requires sophisticated purifying methods. Furthermore, the yield of natural proteins is restricted by their extremely low BAP content. Even though chemical synthesis is the most mature technology for peptide production, the necessity of toxic reagents for their chemical production and lack of specificity are severe drawbacks. On the other hand, recombinant DNA technology uses fewer chemicals and makes the synthesis of these proteins simpler with high yield and purity without any environmental impact [113, 114].

According to multiple studies, recombinant production of BAPs can be categorized into two classes, depending on bioactive peptide gene expression in a particular expression system, either in vivo or in vitro [6]. In the in vivo expression method, the targeted peptide gene is linked to another known carrier protein gene to make the purification simple and to be able to produce a mass amount of the necessary peptide. For instance, ecallantide and desirudin peptides are expressed in yeast [115, 116]. On the other hand, the in vitro expression method, which is a cell-independent system, has the benefit of rapid production of the desired outcome though it is not cost-effective [117]. However, the recent focused method is the engineering of BAPs, due to peptide flexibility and effectiveness. For example, engineered insulin plays a crucial role in type II diabetes with a longer effect than own insulin [118].

One study investigated the recombinant synthesis of the BAP, GIISHR (Gly-Ile-Ile-Ser-His-Arg) with notable antioxidant activity from the muscle of the flawless smooth-hound (Mustelus griseus) [119]. Antioxidant peptides isolated from spotless smooth-hound exhibited good scavenging activities and protected H₂O₂-induced HepG2 cells from oxidative stress by increasing the levels of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase along with decreasing the content of malonaldehyde [4]. The peptide had a strong ability to neutralize hydroxyl, ABTS (2,2′-Azino-bis-(3-ethylbenzotiazoline-6-sulfonic acid)), and superoxide radicals [119]. At the beginning, the strain as host such as E. coli needs to be selected and then the expression vector is designed. Tricine-SDS-PAGE and western blot analysis are employed to assess the amount of expression of the recombinant protein [120], which is followed by trypsin digestion and purification of the peptide [121]. Then, the purified peptide was analyzed by liquid chromatography and their activity was tested by different assays [4].

An antagonistic peptide, Turgincin A is recombinantly produced by the Pichia pastoris strain. This recombinant peptide prevents the growth of all bacteria in the pork meat while preserving the meat's color [21]. Another recent recombinant fusion peptide, CpsA-CpsC-L-ACAN consists of three parts: CpsAo CpsC, the enzymes that produce Streptococcus agalactiae capsules, serine, and glycine, a linker, and ACAN, an anticancer component. As a result, this peptide shows good antimicrobial performance against E. coli and Staphylococcus aureus [22].

3. Antimicrobial Applications of BAPs against Foodborne Pathogens

Both the health of people and the economy are at stake due to the rise in the frequency of foodborne diseases. The presence of harmful bacteria, viruses, fungi, parasites, and toxins in food that is contaminated has been linked to more than 200 various diseases [122]. Due to this, the application of preservatives is required in a wide variety of foods to ensure safety while preserving the product's quality and sensory qualities. In addition, as it was already indicated, efforts are continually made to find natural antimicrobials in order to keep up with the customer demand [123]. In this case, the application of BAPs becomes necessary.

Plant-derived BAPs having antimicrobial properties have been identified and described in a wide range of structural and functional ways up to this point. From a library of cDNA derived from Mexican avocado fruits, PaDef was found and isolated. It is a peptide with defensin-like properties. As PaDef exhibits antibacterial properties against S. aureus and E. coli, it can be used to heal foodborne infections [124]. In a different investigation, four closely similar cysteine-rich peptides with antifungal and antibacterial properties were extracted and described from the grain of Impatiens species balsamina [125]. In addition, these cysteine-rich peptides showed high activity against enteric pathogens such as S. aureus, E. coli, and Salmonella yet showed no cytotoxicity toward human cells. Plants have also been found to contain 2S albumin proteins, another family of AMPs. Pa-AFP-1 was discovered to effectively suppress the growth of filamentous fungi, including Trichoderma harzianum, Colletotrichum gloeosporioides, Aspergillus fumigatus, and Fusarium oxysporum, which were isolated from passion fruit [126, 127]. The next compound is CaThi, an isolated and described thionin-like peptide from chili. According to reports, CaThi is effective against a variety of pathogenic bacteria, including Candida albicans, F. solani, C. tropicalis, and S. cerevisiae [128, 129].

The main enzyme for photorespiration and photosynthesis in plants as well as in other living things is known as ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), which is also the most prevalent protein in the world. RuBisCO is a desirable and long-term resource for BAPs [130]. RuBisCO 407 large subunit-derived peptides ELAAAC (f454-459), and MDN (472-474), as well as the original hydrolysate and portions generated by hydrolyzing RuBisCO with pepsin, all exhibited antimicrobial activity against Gram-positive (L. innocua, Micrococcus luteus, and Bacillus subtilis) and Gram-negative (E. coli) microorganisms [131]. Unquestionably, a revolutionary method for producing BAPs with a variety of positive health effects involves the fermentation by microorganisms of protein from different sources. The BAPs produced by microbial fermentation can be further purified without hydrolysis, and it is less expensive than using enzymes [8].

Gram-positive lactic acid bacteria (LAB) are the source of a wide range of bioactive substances, such as fatty acids, hydrogen peroxide, short-chain peptides, and fatty acids. The importance of LAB in the food and beverage business extends far beyond the manufacture of fermented foods because many of these substances have a bioprotective action against infections and degrading agents [132, 133]. Lactiplantibacillus plantarum, a LAB that is known to produce antimicrobial peptides, has been examined in various investigations to determine whether it has the capacity to inhibit significant foodborne pathogens [134–136]. Research also showed that L. plantarum, cell-free supernatant, and isolated bacteriocins from this strain enhance direct inhibition. In addition, it has been noted that BAPs produced from L. plantarum have the properties of proteolyzing milk proteins [137–139]. S. aureus, L. monocytogenes, E. coli, and S. Typhimurium are only a few of the Gram-positive and Gram-negative foodborne pathogenic organisms that have been found to be inhibited by L. plantarum fermented camel's milk [137, 140, 141]. In addition, a significant amount of low-molecular-weight antimicrobial peptides were found among which 32 of these peptides came from milk proteins in the most effective fraction [138]. Lactobacillus casei ATCC 334 producing BAP-P1, P2, and P4 in the fermented fat kenaf grain had a strong antibacterial action against S. Typhimurium, E. coli, Pseudomonas aeruginosa, S. aureus, and other microorganisms [142]. Bioactive antimicrobial peptides also exhibit antivirulence property activity against foodborne pathogens at subinhibitory concentrations. Various BAPs have bactericidal effects on biofilm formation and can eradicate infections in animal models [143].

Nanoantimicrobials are frequently utilized to treat bacterial infections directly. Nanoantimicrobials, also known as nanoantibiotics, are nanoparticles exhibiting antimicrobial activity or enhancing the activity of encapsulated antimicrobial agents. Chitosan nanoparticles and peptides, known as CNMs, are outstanding new antibacterial medications that are a promising alternative to antibiotics for use against harmful bacteria. By using a digestive epithelial cell framework, the role of CNMs was assessed in the prevention of E. coli O157 infection. CNMs exhibited good bactericidal effects against E. coli O157, according to antibacterial activity testing [144].

Both Gram-positive and Gram-negative bacteria, including, E. coli, L. monocytogenes, S. aureus, P. aeruginosa, and S. enterica were inhibited by the antibacterial activity of BAPs generated by Bifidobacterium lactis BB-12 and Lactobacillus acidophilus LA-5 in milk model medium and their combination cultures [145]. Figure 1 shows the antimicrobial applications of bioactive peptides.

Figure 1.

Schematic illustration of BAPs and their potential antimicrobial applications against foodborne pathogens.

The primary biotechnological tool for producing Brewer's or Baker's biomasses, which are mostly used in the production of fermented foods and beverages, is Saccharomyces cerevisiae. The S. cerevisiae precursor proteins enolase II and glyceraldehyde-3-phosphate dehydrogenase are notable because they released BAPs having antimicrobial properties with the highest scores. In particular, protein-sealing antibacterial peptides that exhibit broad-spectrum activity and may prevent cytotoxicity while also reducing the emergence of microbial resistance ought to be considered a reliable and year-round source for next-generation bioactive substances. S. cerevisiae biomass is a food-grade product that is sold and consumed globally [146].

4. Mode of Action of BAPs against Foodborne Pathogens

Nomura's 1967 identified two mode of actions of biopeptides [147]. One method showed how bacteria might attach to peptides, creating pores or holes in their cell walls. Another method proposed how contact strength damages the chemical and biological structures of afflicted cells [148]. The interaction of peptides with sensitive cells can occur in two ways: (1) cell wall receptors bind to the peptide molecules and it does not affect the physiological makeup of cells or (2) the impacted cells suffer biological and chemical harm [149]. The interaction between positively charged BAPs and the mannan of fungi, lipoteichoic acid of Gram-positive bacteria, and LPS of Gram-negative bacteria is characterized by a significant affinity [150]. Figures 2 and 3 show the possible antimicrobial mechanisms of BAPs.

Figure 2.

Models of membrane-cavity formation. BAPs' direct bactericidal mechanism involves their interaction with negatively charged membranes, which leads to increased cell membrane permeability, rupture of the cell membrane, or the release of internal contents, and ultimately, cell death. The formation of membrane pores may involve the toroidal-pore, aggregate, barrel-stave, and carpet models, respectively. The hydrophobic sections of peptides enter the phospholipid membrane mix with the internal hydrophobic portions of the phospholipid bilayer, leaving the hydrophilic portions exposed to the outside.

Figure 3.

The intracellular modes of action of BAPs. The penetration of BAPs into the cell protoplasm, allowing their interactions with intracellular activities, causes the inhibition of cell wall synthesis, DNA, RNA, and protein synthesis, protein folding, and enzyme activity. Another bactericidal mechanism of certain BAPs is to activate autolysin to destruct cell structures.

4.1. Alteration of Outer Membrane Permeability

BAPs can enter the membrane and perform intracellular functions or permeate the membrane and cause intracellular contents to leak [147, 150]. The interaction of peptides with cell walls is primarily influenced by conformational change and the peptide-lipid ratio [151–154]. In an aqueous solution, alpha-helical peptides attach to the negatively-charged lipid membrane and change its disorganized structure. The stability of disulfide bond bridges in β-sheet peptides is attributed to their lack of conformational changes during interaction with the plasma membrane [155]. The peptide-lipid ratio is another important factor since low values lead peptides to be located parallel to the bacterial cell membrane [156, 157].

Some speculative models of membrane-cavity formation have been put forth, including the barrel-stave, toroidal-pore, carpet, and aggregate models (Figure 2) [147]. In the barrel-stave model, when more peptide binds to the membrane, aggregation and conformational modification take place, leading to a shift in the local phospholipid head groups and thinning of the membrane [68]. During penetration into the phospholipid bilayer, the hydrophilic sections of the peptide helixes face inside, whereas the hydrophobic portions of the β-sheet and α-helical peptides are near the cell membrane phospholipid. The core lumen is formed by paralleling many helical molecules [155]. Unlike the barrel-stave model, the toroidal-pore model involves peptide helices penetrating the cell membrane and interacting with lipids to construct the toroidal-pore complexes. High quantities of locally-gathered peptides cause lipid molecules to bend, which allows both the lipid head groups and peptides anchored inside the core of the lipid to move [68]. While the electrostatic impact of peptides and anionic membrane is essential in the carpet model, significant peptide concentrations must be present to produce micelles and damage the microbial membrane [155]. While the concentration of peptide crosses the threshold, clusters of peptides coat the membrane and break it like a surfactant. In the hydrophobic core of the membrane, neither channel development nor peptide insertion takes place. This action is strong enough to cause cell death by partial or total lysis of the cell membrane [147].

According to the aggregation model, lipids and peptides are compelled to assemble a micelle of the peptide-lipid complex when peptides attach to the anionic cytoplasmic membrane [158]. In comparison to the carpet concept, peptides, lipids, and water in cellular channels allow ions and subcellular components to flow. Cell death results from leakage. These channels might also assist in the transfer of peptides into the cytoplasm, where they can function. This mechanism explains why peptides can act on intracellular substances in addition to the cytoplasmic membrane, which is their primary target [159]. Unlike cationic peptides, the mechanisms underlying anionic peptides are still unknown. Maximin H5's antimicrobial effect against S. aureus has been believed to underlie membrane dissolution [160]. Other reported modes of action also include membrane destruction. For instance, clavanin A embraces the α-helical peptide membrane permeation mode in neutral pH [161]. However, it causes cell death in slightly acidic pH by acting on membrane proteins that keep a constant pH gradient. An essential step for disrupting microbial surfaces is the LPS anchored in the bacterial pathogen's outer membrane [162]. The vital role of the synchronized opening movements of the LPS transport (Lpt) β-taco domain and β-barrel of the LPS transport protein has been shown to facilitate the insertion of LPS into the bacterial surface. Since thanatin stabilizes the β-taco domain, LPS cannot be transported to the cell surface [162].

4.1.1. Alteration of the Intracellular Mechanism of Action

Buforin II, a BAP, containing 21 amino acids, displays antibacterial action against a variety of microorganisms [163]. It shares the same sequence as a piece of the protein called histone H2A, which directly engages nucleic acids [163]. Previous studies have shown that buforin II has the capacity to bind to DNA and RNA, as well as penetrate lipid vesicles in vitro, hence potentially affecting the permeability of the membrane [163]. PR-39, a BAP, isolated from the small intestine of pigs and high in proline and arginine, was discovered to quickly permeate the outer membrane of E. coli [164]. After entering the cytoplasm, PR-39 interferes with the synthesis of proteins, leading to the breakdown of proteins essential for the synthesis of DNA. Consequently, this disruption impairs the process of DNA synthesis. Usually, the proline-enriched BAPs attach to ribosomes and obstruct protein production [165].

According to reports, peptides stop a bacterial intracellular enzyme from working. The bacterium heat shock protein DnaK, which was isolated from protein lysates of E. coli and shown to be selectively bound by pyrrhocoricin, was demonstrated by the Otvos' group [166]. The same team went on to show in a subsequent investigation that pyrrhocoricin prevented DnaK from acting as an ATPase [167]. It was first discovered that human neutrophil peptide-1 could enter both the inner and outer membranes of E. coli and inhibit the making of the bacteria's DNA, RNA, and proteins [168]. The deadly event, it should be noted, seems to be inner membrane permeabilization. The enzymatic activities of D-Ala-D-Ala ligase and alanine racemase are essential for the biosynthesis of D-Ala-D-Ala dipeptide, a key component of lipid II, that serves as a precursor molecule in the formation of peptidoglycan. The antibacterial activity of bacteria may be restricted by cycloserine via the inhibition of D-Ala-D-Ala ligase and alanine racemase [169].

As BAPs exhibit antibacterial activity by membrane or nonmembrane-mediated action either by increasing membrane permeability or pore formation leading to the leakage of intracellular contents, or penetration into the membrane to exert intracellular actions without targeting specific molecules/pathways, it is unlikely to develop bacterial resistance to BAPs [147, 150]. The maximal H5 engages in interactions with bacteria through its N-terminal helical peptide, while the aspartate residues primarily serve a minimal function. As a result of their separation from the membrane surface, they play an important structural role. The hydrogen bonds created during the acetylation of the N- and C-terminal ends of the peptide are what stabilize its -helix structure [170]. Despite cell membrane disintegration and intracellular efflux, the anionic peptide Xlasp-p1 displays wide antibacterial activity against Gram-positive and Gram-negative bacteria [171].

A milk-derived peptide (AMP SSSEESII from α_s2-casein) has been shown in many studies to be able to prevent the development of M. luteus, L. innocua, E. coli, and S. enteritidis. In casein, a different bioactive peptide called IKHQGLPQE reduced the number of harmful microorganisms that are often prevalent in newborn formula [172]. B. subtilis, S. aureus, S. pneumoniae, E. coli, P. aeruginosa, S. dysenteriae, and S. typhimurium have all been reported to be strongly inhibited by the GLSRLFTALK peptide [173]. Mackerel byproducts E. coli and Listeria innocua were both suppressed by SIFIQRFTT [174]. Antioxidant activities [175] and immunomodulation [176] can make BAPs better alternatives for antibiotics [172]. Several haemoglobin-derived peptides possess cytotoxic properties against S. Enteritidis, S. saprophyticus, S. simulants, B. cereus, E. coli, M. luteus, E. faecalis, L. innocua, and S. sonnei. [177, 178].

5. Conclusions and Future Prospects

Several studies have demonstrated the significance of BAPs and their applicability in the pharmacological and pharmaceutical fields. They may also be used in crop development and cosmetology, though to a lesser level [179–183]. These bioactivities, especially the antibacterial potential, can be advantageous to the agri-food sector. This business is constantly in need of the creation of effective and secure substitutes for preservatives and food additives. As a result of the advent of antibiotic resistance, the abuse of antibiotics in livestock farming is additionally a significant worldwide public health issue. Researchers are trying to develop unique, safe, and efficient antimicrobial agents [184–188]. The use of BAPs with antimicrobial capacity appears to be a favorable strategy for concerns relating to both food safety and animal growth promotion [189–191]. With demonstrated action against significant bacteria such as B. subtilis, L. monocytogenes, E. coli, V. parahaemolyticus, P. aeruginosa, S. aureus, K. pneumoniae, and S. enterica, the use of BAPs produced from dietary proteins against foodborne pathogens has a lot of potential. When evaluating the application of BAPs having antimicrobial properties, BAPs as food additives or drugs, it is important to keep in mind that the majority of studies have been conducted in vitro, and further research is required to assess the in vivo combinations and how they interact with food substrates [192]. Another problem is that BAPs may lose their bioactivity as a result of interactions with other food matrix constituents, food manufacturing, or the intestinal environment. Therefore, when developing functional foods containing these peptides, it is necessary to assess the impact of food manufacturing conditions on the biological activity as well as the availability of these peptides. In addition, it is necessary to examine how these peptides interact with other ingredients once they have been added to the food matrix. It is possible to consider the controlled delivery systems such as microparticulate, nanoemulsion, and nanostructured lipid carriers or chemical changes such as the cyclization of the structures of BAPs that are vulnerable to digestive enzymes or thermal treatment [184]. The feasibility of using controlled delivery methods, such as microparticulate, nanoemulsion, and nanostructured lipid carriers, or implementing chemical modifications, such as cyclization of bioactive peptide structures, to protect against the effects of digestive enzymes or heat treatment may be contemplated [193]. BAPs are intriguing compounds with a wide range of uses because of their antioxidant, anticancer, antihypertensive, antihyperpigmentation, anti-inflammatory, antidiabetic, intestine-modulating, hypocholesterolemic, and antibiotic properties, along with others. BAPs can modulate the composition of gut microbiota facilitating the proliferation of those with antiobesity effects that exert antiobesity effects by controlling the energy balance of the host and food intake along with suppressing the growth of proobesity gut bacteria. Future studies should therefore concentrate on encouraging the commercial manufacturing of stable, plant- and microbe-based BAPs that may be used in a variety of food matrices without impairing food quality or bioavailability along with controlling foodborne pathogens. Opportunities and difficulties are constantly interconnected, and sufficient scientific evidence supports the idea that BAPs produced from plant materials and microbial sources may exhibit a variety of biological and functional features, highlighting their enormous potential in the food industry as well as for controlling the emergence of foodborne pathogens in the future.

Data Availability

No data were used to support the study.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

Anowar Khasru Parvez and Md. Amdadul Huq contributed equally as the first author of this manuscript.