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Bacteriocin

Bacteriocins are ribosomally synthesized antimicrobial peptides or proteins produced by various bacteria, primarily to inhibit or kill closely related or similar bacterial strains as a natural competitive strategy in microbial ecosystems.^[1]^[2] These compounds are typically small, ranging from less than 5 kDa to over 30 kDa, and exhibit specificity toward target bacteria while the producing strain is protected by self-immunity mechanisms.^[3] First identified in the early 20th century through studies on colicins from Escherichia coli, bacteriocins have since been recognized for their role in bacterial antagonism and their potential as alternatives to traditional antibiotics.^[2] Bacteriocins are produced by a wide array of bacteria, including Gram-positive species like lactic acid bacteria (Lactococcus lactis, Lactobacillus plantarum) and Gram-negative ones such as Escherichia coli, with production occurring during late-exponential to early-stationary growth phases under conditions influenced by nutrient availability and cell density.^[3]^[1] They are synthesized via ribosomal pathways, often encoded on plasmids or chromosomal genes, and secreted extracellularly through dedicated transporters like ATP-binding cassette (ABC) systems or the general secretion pathway, sometimes involving post-translational modifications such as lanthionine formation.^[2] Classification systems vary but commonly divide them into three main classes: Class I (modified peptides like lantibiotics, e.g., nisin, <5 kDa and heat-stable), Class II (unmodified or minimally modified small peptides, <10 kDa, heat-stable, subdivided into pediocin-like, two-peptide, and circular types), and Class III (larger, heat-labile proteins >30 kDa, either lytic or non-lytic).^[3] Recent updates propose a more detailed framework with 12 subclasses for Class I ribosomally synthesized and post-translationally modified peptides (RiPPs) and three for Class II.^[2] The mechanisms of action for bacteriocins primarily involve targeting the cell envelope of susceptible bacteria, such as forming pores in cytoplasmic membranes leading to ion leakage and cell death, binding to lipid II to inhibit cell wall synthesis, or disrupting essential cellular processes like protein synthesis.^[1]^[3] These actions are often receptor-mediated, with specificity determined by ionic interactions or docking to surface proteins, rendering them effective against Gram-positive pathogens like Listeria monocytogenes and Staphylococcus aureus, though some, like microcins, target Gram-negatives.^[2] In applications, bacteriocins serve as biopreservatives in food industries (e.g., nisin, approved by the FAO/WHO in 1969 for use in over 50 countries), therapeutics against multidrug-resistant infections such as MRSA, and probiotics or immunomodulators in veterinary medicine for conditions like bovine mastitis.^[3] Emerging research highlights their prospects in agriculture for plant protection, aquaculture growth promotion, and microbiome modulation, with over 8,000 publications underscoring their growing impact by 2023.^[2]

Overview

Definition and Characteristics

Bacteriocins are ribosomally synthesized antimicrobial peptides or proteins produced by bacteria, which exhibit bactericidal or bacteriostatic activity primarily against closely related strains through a narrow spectrum of action.^[4]^[5] These molecules are secreted extracellularly and often include dedicated immunity mechanisms that protect the producing bacterium from self-killing.^[4] Key characteristics of bacteriocins include a wide range of molecular weights, typically under 5 kDa for smaller peptide forms and exceeding 5–10 kDa for larger protein variants, influencing their stability and mode of action.^[6]^[4] Many bacteriocins demonstrate heat stability, particularly the smaller peptides that retain activity after exposure to temperatures up to 100°C for short durations, whereas larger proteins tend to be more heat-labile.^[5] They often possess cationic and amphiphilic properties, enhancing solubility in aqueous environments and facilitating interaction with target bacterial membranes.^[4] Post-translational modifications, such as the formation of lanthionine bridges in certain peptides, contribute to their structural rigidity and potency.^[5] In contrast to broad-spectrum antibiotics, which are typically secondary metabolites derived from fungi or semi-synthetic sources and affect a wide range of microorganisms, bacteriocins display high specificity for bacterial competitors, frequently employing receptor-mediated uptake and targeted killing mechanisms that minimize off-target effects.^[4]^[6] This targeted nature reduces the likelihood of widespread resistance development compared to traditional antibiotics.^[4] From an evolutionary perspective, bacteriocins play a crucial role in microbial ecology by serving as weapons in chemical warfare among bacterial populations, enabling producers to secure ecological niches, limit competitor growth, and modulate community dynamics for resource acquisition.^[5]^[6]

Historical Discovery

The discovery of bacteriocins began in 1925 when Belgian microbiologist André Gratia identified antimicrobial activity produced by one strain of Escherichia coli that inhibited the growth of a related strain, marking the first observation of what would later be termed colicins.^[5] This finding arose during efforts to explore bacterial antagonism as a means to combat infections, predating the widespread use of antibiotics.^[7] Gratia's work laid the groundwork for recognizing bacteriocins as proteinaceous substances with strain-specific toxicity, though the term "bacteriocin" itself was not coined until later. In the mid-20th century, French researchers advanced the understanding of colicins as proteinaceous toxins. In 1946, André Gratia and Pierre Frédéricq coined the term "colicin" to describe these substances and demonstrated their protein nature through enzymatic digestion experiments, while also noting their narrow spectrum of activity against related E. coli strains.^[8] Throughout the 1950s, Frédéricq and colleagues further characterized colicins by identifying multiple types (e.g., colicins E and K) based on their receptor specificity and bactericidal effects, establishing them as models for studying bacterial antagonism.^[9] These efforts highlighted colicins as plasmid-borne traits, influencing early genetic studies on bacterial inheritance. The 1960s and 1970s saw the expansion of bacteriocin research beyond Gram-negative bacteria to include Gram-positive producers, with a focus on lantibiotics. Nisin, first isolated in 1928 from Lactococcus lactis (then Streptococcus lactis) during studies of milk fermentation inhibitors, gained recognition as a prototypical lantibiotic after its structure—featuring lanthionine bridges—was partially elucidated in the 1950s and fully detailed in 1971.^[10] Reviews in this era, such as Tagg et al. (1976), emphasized bacteriocins from Gram-positive lactic acid bacteria, broadening the field to include diverse antimicrobial peptides with applications in food preservation.^[11] Key milestones in the 1980s involved genetic analyses revealing plasmid-encoded production and regulation of bacteriocins, particularly in lactic acid bacteria. Studies demonstrated that genes for bacteriocin synthesis, export, and immunity were often clustered on plasmids, enabling conjugal transfer and facilitating industrial strain engineering.^[12] By the 1990s, standardized naming conventions and classifications emerged, with Klaenhammer (1993) proposing a system dividing Gram-positive bacteriocins into Class I (lanthionine-containing, like nisin), Class II (small heat-stable non-lantibiotics), and Class III (large heat-labile proteins), providing a framework for ongoing research.^[12]

Biosynthesis and Production

Biosynthetic Mechanisms

Bacteriocins are primarily ribosomally synthesized antimicrobial peptides and proteins produced by bacteria, involving the translation of precursor peptides encoded by structural genes within biosynthetic gene clusters. These precursors typically consist of an N-terminal leader peptide and a C-terminal core region that undergoes modification to yield the mature bacteriocin. However, leaderless bacteriocins, a subclass primarily among class II peptides, lack the leader peptide and are directly translated as the mature form, exported via the general Sec-dependent pathway.^[13] For instance, in lantibiotics such as nisin, the structural gene nisA (analogous to lanA in general nomenclature) encodes a 57-amino-acid prepeptide, where the leader sequence directs subsequent processing while the core peptide forms the active structure.^[14]^[15] Post-translational modifications are crucial for bacteriocin maturation, particularly in modified classes like lantibiotics, where specific enzymatic steps confer stability and activity. In class I lantibiotics, dehydration of serine and threonine residues to dehydroalanine (Dha) and dehydrobutyrine (Dhb) is catalyzed by LanB dehydratases, followed by intramolecular cyclization where cysteine thiols attack these unsaturated amino acids to form lanthionine (Ala-Lan-Ala) or methyllanthionine (Abu-MeLan-Ala) thioether bridges, mediated by zinc-dependent LanC cyclases. The leader peptide is then cleaved by dedicated proteases, such as the Ser/Thr protease LanP (e.g., NisP for nisin), typically at a specific recognition site like Gly-Ala-(Xxx)₂-Arg, releasing the mature peptide only after full modification. These processes ensure the formation of rigid, heat-stable structures, as exemplified by nisin's five interlocking rings.^[14]^[15]^[16] While most bacteriocins rely on ribosomal synthesis, non-ribosomal peptide synthetase (NRPS) pathways are rare and typically associated with distinct antibiotic classes rather than canonical bacteriocins, though some hybrid systems may incorporate NRPS-like modules in specialized producers. Export of mature bacteriocins occurs via dedicated systems to prevent intracellular toxicity, often involving ATP-binding cassette (ABC) transporters that couple secretion with final processing. For example, in many Gram-positive bacteriocins like nisin, bifunctional ABC transporters such as LanT (e.g., NisT) facilitate leader peptide removal during translocation across the membrane, while dedicated ABC complexes like AS-48EFGH handle circular bacteriocins such as enterocin AS-48. Alternatively, some unmodified bacteriocins, such as certain class II peptides, utilize the general Sec-dependent secretory pathway for export. These mechanisms ensure efficient production and self-immunity in the host bacterium.^[17]^[18]^[19]

Genetic Regulation

The genetic regulation of bacteriocin production is primarily orchestrated through clustered gene operons that coordinate the expression of structural, modification, transport, immunity, and regulatory components. In many bacteriocin systems, such as the well-studied nis operon in Lactococcus lactis responsible for nisin biosynthesis, the genes are organized into divergent transcriptional units: the nisABTCPRIFEG cluster includes the structural gene nisA for the pre-nisin precursor, modification genes (nisB and nisC) for post-translational alterations, transport genes (nisT and nisP for secretion and proteolysis), immunity genes (nisI and nisFEG for producer protection), and regulatory genes (nisR and nisK forming a two-component system).^[20] This operon structure ensures synchronized expression, with promoters driving polycistronic transcription to optimize resource allocation during production phases. Similar organization is observed in other lantibiotics and class II bacteriocins, where regulatory elements like promoters and terminators maintain tight control over the entire biosynthetic pathway.^[21] A key regulatory mechanism is quorum sensing, which links bacteriocin production to producer cell density, preventing wasteful expression in low-population environments. In nisin-producing strains, the mature nisin peptide itself serves as an autoinducer, binding to the histidine kinase sensor NisK, which phosphorylates the response regulator NisR to activate transcription of the nis operon at a threshold concentration corresponding to high cell density.^[22] This density-dependent induction is conserved across many bacteriocin systems, including those in streptococci where competence-stimulating peptides (CSPs) or BlpC pheromones regulate blp and com operons, coordinating bacteriocin release with population-level behaviors like biofilm formation or competence development.^[23] Such quorum sensing circuits enhance ecological fitness by synchronizing antimicrobial deployment only when competitors are likely present.^[24] Immunity to self-produced bacteriocins is genetically encoded within the same operons to protect the producer, typically through dedicated immunity proteins expressed constitutively or inducibly. For instance, in colicin E2 systems of Escherichia coli, the immunity gene cei encodes a small protein that binds the colicin in the periplasm, neutralizing its nuclease activity and preventing host cell death; this gene is co-transcribed with the structural cea and lysis cel genes but under separate promoter control for balanced expression.^[25] Immunity genes like nisI in the nisin cluster produce lipoprotein anchors that sequester the lantibiotic on the cell surface, ensuring producer survival during high-yield production phases.^[26] Bacteriocin genes are predominantly encoded on plasmids, facilitating horizontal transfer and rapid dissemination among bacterial populations, though chromosomal integration occurs in some cases for stable inheritance. Plasmid-borne loci, such as those for colicins on group B plasmids in Enterobacteriaceae, include mobility elements like transposons that promote conjugal spread, enhancing the "selfish genetic element" nature of these systems.^[27] In contrast, chromosomal encoding is seen in bacteriocins like mutacin II from Streptococcus mutans, where integration into the genome provides heritable protection without reliance on plasmid stability.^[21] This dual encoding strategy reflects evolutionary trade-offs between mobility and persistence in diverse microbial niches.^[28]

Classification

Methods of Classification

Bacteriocins are systematically classified using multiple criteria to account for their diversity, including the producing organism, molecular weight, biosynthesis pathways, structural features, mechanisms of action, and genetic characteristics.^[12] The primary distinction is based on the Gram status of the producer, separating bacteriocins from Gram-positive bacteria (e.g., lactic acid bacteria producing lantibiotics) and Gram-negative bacteria (e.g., colicins from Escherichia coli).^[29] This approach reflects differences in cell wall architecture and export mechanisms, with Gram-positive bacteriocins often being smaller and more heat-stable.^[30] Molecular weight serves as a key physicochemical criterion, categorizing bacteriocins into small peptides (<5 kDa, such as lantibiotics) and larger proteins (>30 kDa, such as bacteriolysins).^[31] Biosynthesis methods further refine this, distinguishing ribosomally synthesized and post-translationally modified peptides (RiPPs, predominant in most classes) from rare non-ribosomally synthesized ones.^[5] Structural attributes, including modifications like lanthionine bridges in lantibiotics or cyclic lasso formations, versus unmodified linear peptides, provide additional granularity.^[12] Classification by killing mechanisms highlights functional diversity, including pore-forming activity that disrupts membrane potential, inhibition of cell wall synthesis (e.g., targeting lipid II), and enzymatic actions like nuclease or cell wall degradation.^[32] Genetic and phylogenetic approaches analyze operon structures, sequence homology in biosynthetic gene clusters, and evolutionary relationships via tools like antiSMASH, revealing horizontal gene transfer patterns.^[33] Early schemes evolved from colicin-focused classifications in the 1960s, emphasizing Gram-negative producers, to broader systems like Klaenhammer's 1993 framework for lactic acid bacteriocins, which used molecular weight, thermostability, and modifications to define three main classes.^[12] Modern multi-criteria systems, refined in the 2000s and 2010s, integrate genomic data and structural insights for a more comprehensive taxonomy.^[31]

Gram-Negative Bacteriocins

Gram-negative bacteriocins represent a diverse group of antimicrobial proteins and peptides produced by Gram-negative bacteria, primarily targeting closely related species to confer competitive advantages in microbial communities. Unlike their Gram-positive counterparts, these bacteriocins often face unique challenges in export due to the complex outer membrane of Gram-negative producers, leading to specialized secretion mechanisms. They are broadly classified into small peptide-based microcins, larger modular colicin-like proteins, and phage tail-like tailocins, each exhibiting distinct structural and functional properties.^[7]^[34] Microcins are the smallest subclass of Gram-negative bacteriocins, typically under 10 kDa, and are highly stable peptides produced mainly by Enterobacteriaceae such as Escherichia coli. These ribosomally synthesized peptides undergo post-translational modifications, such as cyclization or siderophore conjugation, enhancing their stability and activity. A prominent example is microcin J25, a lasso-structured peptide that inhibits bacterial RNA polymerase by mimicking DNA in the transcription initiation complex, thereby blocking RNA synthesis in sensitive cells. Another key microcin, B17, targets DNA gyrase to induce DNA damage. Microcins are frequently encoded by plasmid or chromosomal gene clusters that include genes for production, self-immunity, and export, often via ABC transporter-dependent type I secretion systems or the TolC outer membrane channel. Their host range is generally narrow, affecting related enterobacteria like Salmonella and Shigella, which underscores their role in niche competition within the gut microbiome.^[35]^[36]^[37] Colicin-like bacteriocins, in contrast, are larger proteins ranging from 20 to 90 kDa, featuring a modular architecture with distinct domains for receptor recognition, translocation across the outer membrane, and cytotoxic activity. Produced predominantly by E. coli and related species, these bacteriocins are plasmid-encoded and include genes for the toxin, immunity protein, and lysis components to facilitate release. For instance, colicin E1 forms voltage-gated pores in the inner membrane, leading to depolarization and cell death in target bacteria. Translocation typically exploits host uptake systems like the TonB-dependent transporters or Tol proteins, allowing entry without dedicated secretion machinery in some cases. This subclass exhibits high specificity, killing only strains with compatible receptors, which limits their spectrum but enhances precision in ecological interactions. Examples extend beyond E. coli to klebicins in Klebsiella and similar proteins in Yersinia.^[38]^[34]^[7] Tailocins, also known as R- and F-type pyocins in certain contexts, are high-molecular-weight, phage tail-like nanostructures produced by various Gram-negative bacteria, notably Pseudomonas aeruginosa. These non-contractile (F-type) or contractile (R-type) assemblies lack phage heads and genetic material, consisting instead of a tail tube, sheath, baseplate, and receptor-binding tail fibers that recognize lipopolysaccharide (LPS) on target cells. Upon binding, R-type tailocins contract to inject the tube into the membrane, disrupting ion balance and causing rapid lysis. Encoded chromosomally in operons responsive to SOS signals like DNA damage, tailocins are released through producer cell lysis mediated by holin-like proteins. Pyocins such as S1 and R1 from P. aeruginosa exemplify this group, with narrow host ranges confined to closely related strains, enabling targeted killing in polymicrobial environments like biofilms. Their production imposes a fitness cost on producers due to lysis, balancing virulence with ecological benefits.^[39]^[40]^[41] A hallmark of Gram-negative bacteriocins is their frequent plasmid-based encoding, which facilitates horizontal transfer and rapid dissemination within populations, though chromosomal loci are common for tailocins. Export mechanisms vary: type I (ABC) and type II (Sec-dependent) secretion for microcins and colicins, while tailocins rely on lytic release. Collectively, these features contribute to their species-specific activity, with host ranges often restricted to the producer's genus or closer, minimizing off-target effects in diverse microbial habitats.^[35]^[34]^[39]

Gram-Positive Bacteriocins

Bacteriocins produced by Gram-positive bacteria, primarily lactic acid bacteria such as Lactococcus lactis and Lactobacillus species, as well as Bacillus and Streptococcus species, are diverse antimicrobial agents that target other Gram-positive microbes through membrane disruption or enzymatic degradation.^[42] These bacteriocins are typically ribosomally synthesized and classified into four main classes based on structural complexity, size, and post-translational modifications, with a focus on their heat stability and modification status.^[43] This classification helps distinguish their biosynthesis pathways and mechanisms, though overlaps exist due to emerging variants.^[44] Class I bacteriocins, known as lantibiotics, are small peptides under 5 kDa that undergo extensive post-translational modifications, including the formation of lanthionine and methyllanthionine bridges that create rigid ring structures essential for stability and activity.^[42] These modifications involve dehydration of serine/threonine residues followed by intramolecular thioether bond formation with cysteines, rendering them heat-stable and resistant to proteolysis.^[14] Lantibiotics are subdivided into subclasses based on structure: subclass Ia includes elongated, cationic peptides like nisin A from Lactococcus lactis, which features five thioether rings (including lanthionine and methyllanthionine types) that facilitate pore formation in target membranes; subclass Ib comprises globular, often anionic peptides such as mersacidin from Staphylococcus epidermidis, which inhibit cell wall synthesis by binding lipid II intermediates.^[45] A further subclass, Type II lantibiotics, consists of two-component systems like lacticin 3147 from Lactococcus lactis, where synergistic peptide pairs enhance potency through cooperative membrane insertion.^[43] Class II bacteriocins are unmodified or minimally modified peptides ranging from 3 to 10 kDa, characterized by their heat stability and cationic nature, which promotes interaction with negatively charged bacterial membranes.^[42] Subclass IIa, the pediocin-like bacteriocins, are linear peptides with a conserved YGNGV motif in their N-terminal domain, exhibiting strong anti-Listeria activity; a representative example is pediocin PA-1 from Pediococcus acidilactici, which forms pores by targeting the mannose phosphotransferase system in sensitive cells.^[43] Subclass IIb includes synergistically acting two-peptide bacteriocins, such as lactococcin G from Lactococcus lactis, where the α and β peptides (each around 40 residues) must be present in equimolar ratios to disrupt membrane potential effectively.^[42] Other subclasses encompass leaderless (IIc) and miscellaneous linear forms, broadening the diversity within this heat-stable group.^[46] Class III bacteriocins consist of large, heat-labile proteins exceeding 30 kDa, often functioning as enzymes that degrade target cell components rather than forming pores.^[42] These are further divided into IIIa (bacteriolytic, with muramidase or endopeptidase activity) and IIIb (non-lytic, interfering with metabolism); for instance, megacin A-216 from Bacillus megaterium is a approximately 50 kDa protein with phospholipase A2 activity that disrupts membranes in sensitive Bacillus strains, leading to cell death.^[47] Another example, lysostaphin from Staphylococcus simulans, is a zinc-dependent endopeptidase that hydrolyzes the pentaglycine cross-bridges in staphylococcal cell walls.^[42] Class IV bacteriocins represent a smaller, more heterogeneous group of complex macromolecules that incorporate lipid or carbohydrate moieties, making them sensitive to enzymatic digestion but effective in membrane perturbation.^[43] These include glycosylated peptides like glycocin F from Lactobacillus plantarum, where O-linked glycosylation enhances stability and solubility, or lipidated forms, enhancing their interaction with target membranes.^[46] Though less common, these modifications distinguish Class IV from simpler peptide classes and highlight evolutionary adaptations in producer strains like Lactobacillus.^[44]

Mechanisms of Action

General Modes of Action

Bacteriocins exert their antimicrobial effects through diverse mechanisms that primarily target the cell envelope or intracellular processes of susceptible bacteria, leading to cell death or growth inhibition. These modes of action can be broadly categorized into membrane disruption and intracellular targeting, with effects often modulated by concentration. For instance, many bacteriocins form pores or disrupt membrane integrity, causing ion leakage and dissipation of the proton motive force, while others translocate into the cytoplasm to inhibit essential enzymes or degrade nucleic acids.^[4]^[48]^[49] A primary mode involves membrane disruption via pore formation, which leads to depolarization and leakage of cellular ions such as potassium. This can occur through the barrel-stave model, where amphipathic helices aggregate to form a transmembrane pore, as seen in colicin A, or the carpet model, in which peptides cover the membrane surface, inducing detergent-like lysis without deep insertion, exemplified by pediocin PA-1 binding to mannose phosphotransferase systems. Such disruptions collapse the electrochemical gradient across the membrane, halting ATP synthesis and causing rapid cell death.^[49]^[48]^[4] Intracellular targeting represents another key mechanism, where bacteriocins inhibit vital cellular processes after translocation. DNase and RNase activities degrade DNA or RNA, respectively; for example, colicin E7 acts as a DNase to cleave double-stranded DNA, while colicin E3 functions as an RNase targeting 16S rRNA to block protein synthesis. Additionally, some bacteriocins interfere with cell wall synthesis by blocking peptidoglycan precursors, as in colicin M, which hydrolyzes lipid-linked intermediates in the periplasm, or nisin, which binds lipid II to prevent its incorporation into the cell wall. These actions often result in energy dissipation without immediate lysis, starving the cell of essential metabolites.^[49]^[50]^[4] The lethality of bacteriocins is frequently dose-dependent, exhibiting bacteriostatic effects at low concentrations by partially disrupting membrane potential or metabolic pathways, and bactericidal effects at higher levels through complete pore formation or extensive nucleic acid damage. For instance, nisin demonstrates nanomolar inhibitory activity that escalates with dose, enhancing membrane permeabilization against Gram-positive targets. This variability underscores the bacteriocins' efficiency as targeted antimicrobials, often requiring only a single molecule to kill a sensitive cell in pore-forming cases.^[4]^[48]^[49]

Target Specificity and Immunity

Bacteriocins achieve selective targeting primarily through receptor-mediated binding to specific components on the surface of susceptible bacterial cells, which restricts their antimicrobial activity to closely related strains and minimizes off-target effects. In Gram-positive bacteria, the lantibiotic nisin exemplifies this specificity by binding to lipid II, an essential precursor in peptidoglycan biosynthesis, thereby docking onto the cell wall synthesis machinery and facilitating pore formation or inhibition of cell wall assembly.^[51] Similarly, in Gram-negative bacteria, colicins such as colicin N utilize outer membrane porins like OmpF as receptors; the receptor-binding domain of colicin N interacts with multiple sites on the OmpF trimer, enabling initial attachment and subsequent translocation across the outer membrane.^[52] This precise receptor interaction ensures that bacteriocins primarily affect phylogenetically similar competitors, enhancing their role in microbial niche competition without broadly disrupting unrelated microbial communities.^[53] To prevent self-intoxication, bacteriocin-producing cells express dedicated immunity proteins encoded by genes typically located adjacent to the bacteriocin structural genes in the same operon. These proteins confer protection by directly binding to the bacteriocin molecule, often sequestering its toxic domain and preventing interaction with the producer's cellular targets; for instance, the immunity protein for colicin E3 tightly associates with the colicin in the periplasm, blocking its nuclease activity with femtomolar affinity.^[8] In pediocin-like bacteriocins from Gram-positive producers, the immunity protein forms a complex that inserts into the membrane pore formed by the bacteriocin, effectively blocking ion leakage and maintaining cellular integrity.^[54] This mechanism is highly specific, as immunity proteins generally do not protect against non-cognate bacteriocins, underscoring the tailored nature of producer self-protection.^[53] Beyond dedicated immunity proteins, additional self-immunity strategies in bacteriocin producers include modifications to receptor sites or active export systems that reduce intracellular accumulation of the toxin. For example, some producers alter their receptor proteins, such as mutations in mannose phosphotransferase systems that prevent binding of class IIa bacteriocins while preserving essential functions.^[55] ABC transporters, often involved in bacteriocin secretion, also contribute to immunity by rapidly exporting the peptide from the producer cell, as seen in lantibiotic systems where the transporter recognizes and expels both the bacteriocin and its associated immunity components.^[56] These layered defenses ensure robust protection without compromising the producer's fitness. The specificity and immunity mechanisms of bacteriocins reflect ongoing co-evolution between toxin production, resistance, and self-protection genes, driving microbial diversity in competitive environments. Immunity genes have co-evolved tightly with bacteriocin loci, often through horizontal gene transfer of operons containing both toxin and immunity elements, allowing rapid adaptation to selective pressures from rival bacteriocins.^[57] In response, target bacteria evolve resistance via receptor mutations or accessory immunity factors, which in turn selects for bacteriocin variants with altered binding specificities, as evidenced in studies of colicin diversity where toxin-immunity pairs diversify to counter emerging resistances.^[58] This arms-race dynamic promotes genetic mosaicism in bacterial genomes, enhancing ecological resilience in polymicrobial communities.^[59]

Applications

Food Preservation

Bacteriocins play a significant role in food preservation by inhibiting spoilage organisms and pathogens, particularly in perishable products like dairy and meat. Nisin, a lantibiotic produced by Lactococcus lactis, is the most widely used bacteriocin and has been affirmed as generally recognized as safe (GRAS) by the U.S. Food and Drug Administration (FDA) since 1988 for applications in pasteurized cheese spreads, processed cheese, and canned foods. It is effective against Gram-positive bacteria, including Listeria monocytogenes and Clostridium species, at concentrations up to 250 ppm (250 mg/kg) in finished dairy products, where it extends shelf life by preventing outgrowth of these contaminants during storage.^[60] Other bacteriocins, such as pediocin PA-1 produced by Pediococcus acidilactici, have been approved by the FDA for use in meat products, including sausages and ready-to-eat meats, to control Listeria growth and reduce spoilage. Commercial formulations like ALTA 2431, containing pediocin PA-1, are applied at levels that achieve reductions in pathogen counts in vacuum-packaged meats stored at refrigeration temperatures. In dairy applications, enterocins from Enterococcus species, such as enterocin A and B, are utilized through bacteriocin-producing starter cultures in cheese and yogurt production, enhancing inhibition of unwanted bacteria without direct addition of purified peptides.^[61]^[62]^[63] Bacteriocins often exhibit synergistic effects when combined with hurdle technologies, such as low pH, mild heat treatments, or high-pressure processing, which broaden their antimicrobial spectrum and lower required dosages for efficacy. For instance, nisin combined with organic acids like citric acid at pH 5.0 enhances inhibition of Clostridium botulinum spores in canned vegetables, achieving greater log reductions than either alone. The European Food Safety Authority (EFSA) has approved nisin (E 234) for use in various foods at levels up to 25 mg/kg in heat-treated meats and 12.5 mg/kg in unripened cheeses, while pediocin benefits from qualified presumption of safety status for producing strains. As of 2024, the FDA granted GRAS status to a pediocin PA-1 analog for expanded use in meat, poultry, and dairy products.^[64]^[65]^[66]^[67] However, challenges include potential flavor alterations from producing strains in non-fermented foods and the risk of resistance development in target bacteria, necessitating careful formulation and monitoring.

Agricultural and Environmental Uses

Bacteriocins have emerged as promising agents for controlling plant diseases in agriculture, offering targeted antimicrobial activity against phytopathogens without the broad-spectrum effects of chemical pesticides. For instance, a class II bacteriocin produced by Bacillus velezensis HN-Q-8 has demonstrated efficacy against potato common scab caused by Streptomyces species, reducing disease severity in potato tubers.^[68] In rhizosphere engineering, bacteriocins from Gram-positive bacteria such as Bacillus thuringiensis play a key role in modulating microbial communities to protect plant roots from pathogenic invasion. These peptides inhibit competitor bacteria in the soil microbiome, promoting the colonization of beneficial microbes that enhance nutrient uptake and disease resistance in crops like legumes and cereals. Studies have shown that bacteriocin-producing strains can improve plant growth and stress tolerance in soybean.^[69]^[70] Beyond plant protection, bacteriocins contribute to environmental bioremediation by aiding in pollutant degradation. In hydrocarbon-contaminated soils, purified bacteriocins from Lactobacillus acidophilus have been applied, achieving up to 89% degradation of petroleum hydrocarbons over 7 days. This approach enhances the efficiency of natural attenuation processes in marine and terrestrial environments.^[71] In aquaculture, bacteriocins provide an effective strategy against Vibrio species, major pathogens in fish and shellfish farming that cause vibriosis and significant economic losses. Probiotic strains producing bacteriocins, such as pediocin from Pediococcus or plantaricin from Lactobacillus plantarum, inhibit V. harveyi and V. alginolyticus by pore formation in their cell membranes, reducing mortality rates in tilapia and shrimp in tank trials. Field applications in pond systems during the 2010s demonstrated sustained pathogen control without residue accumulation, supporting healthier fish stocks.^[72]^[73] The primary advantages of bacteriocins in these contexts lie in their eco-friendly profile as biodegradable, host-specific antimicrobials that degrade rapidly in soil and water, posing minimal risk to non-target organisms compared to synthetic pesticides. Field trials of Bacillus-derived bacteriocins have reported reductions in disease incidence alongside improved soil microbial diversity, underscoring their role in integrated pest management for resilient agricultural and environmental systems.^[69]^[70]

Human Health Relevance

Role in Microbiome Dynamics

Bacteriocins play a crucial role in maintaining the balance of bacterial communities within human-associated microbiomes by selectively inhibiting pathogenic or competing bacteria while sparing beneficial commensals. Produced by various commensal species, these antimicrobial peptides facilitate microbial competition and colonization resistance, thereby shaping the composition and diversity of microbiomes in sites such as the gut, vagina, oral cavity, and skin. This ecological function helps prevent dysbiosis, a state of microbial imbalance often associated with disease, by promoting stable, health-associated communities.^[74] In the vaginal microbiome, Lactobacillus species dominate the healthy flora and produce bacteriocins that inhibit pathogens like Gardnerella vaginalis, a key contributor to bacterial vaginosis. Approximately 80% of tested vaginal Lactobacillus strains exhibit bacteriocin activity against G. vaginalis, helping to maintain Lactobacillus dominance and reduce pathogen overgrowth. For instance, lactocin 160 from Lactobacillus rhamnosus targets G. vaginalis, supporting microbial stability and preventing dysbiosis.^[75]^[76] Within the gut microbiome, colonic bacteriocins contribute to shaping microbiota diversity by modulating interactions among resident bacteria, particularly in contexts like inflammatory bowel disease (IBD). Bacteriocins such as microcin J25 from Escherichia coli alter gut microbiota composition, attenuating inflammation and improving barrier function in models of colitis, thereby enhancing resistance to dysbiosis. Studies indicate that bacteriocin-producing probiotics, including those from lactic acid bacteria, correct gut dysbiosis in IBD by promoting beneficial taxa and inhibiting pathogens, which supports overall microbial diversity.^[77]^[78] In the oral and skin microbiomes, bacteriocins inhibit biofilm formation and pathogen colonization, aiding in the prevention of conditions like dental caries and wound infections. Oral bacteriocins, such as lantibiotics from Streptococcus salivarius, target cariogenic species like Streptococcus mutans, limiting biofilm development on teeth and maintaining a balanced oral community. On the skin, bacteriocins like lugdunin from Staphylococcus epidermidis suppress Staphylococcus aureus growth at wound sites, reducing infection risk and promoting healing while preserving commensal diversity; similarly, Lactobacillus plantarum-derived bacteriocins aid in suppressing S. aureus infections in wounds.^[79]^[80]^[81] Ecologically, bacteriocins enhance dysbiosis resistance across microbiomes by selectively eliminating susceptible competitors, with low bacteriocin activity linked to increased infection susceptibility. For example, lantibiotic-producing bacteria bolster microbiome resilience against pathogens like Klebsiella pneumoniae and Clostridium difficile, preventing sustained dysbiosis; reduced bacteriocin production in commensals has been associated with higher rates of gastrointestinal and skin infections. This selective antimicrobial action underscores bacteriocins' role in fostering stable microbial ecosystems without broad disruption.^[82]^[83]

Therapeutic and Clinical Potential

Bacteriocins have emerged as promising alternatives to traditional antibiotics, particularly in combating multidrug-resistant (MDR) pathogens. Nisin, a well-studied lantibiotic produced by Lactococcus lactis, exhibits potent activity against Gram-positive bacteria, including MDR strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), by forming pores in their cell membranes and disrupting lipid II-dependent peptidoglycan synthesis.^[84] Derivatives of nisin, engineered for enhanced stability and potency, have shown improved efficacy against these pathogens in preclinical models, reducing minimum inhibitory concentrations while maintaining low toxicity to host cells.^[85] For Gram-negative bacteria, colicin-like bacteriocins such as pyocins from Pseudomonas aeruginosa and klebicins from Klebsiella and related species offer therapeutic potential by depolarizing the inner membrane or degrading nucleic acids in pathogens like MDR P. aeruginosa and K. pneumoniae, with in vivo studies demonstrating reduced bacterial loads in infection models without significant off-target effects.^[86] Clinical applications of bacteriocins remain limited but encouraging, with nisin advancing furthest in human trials. A small randomized clinical study in 2008 evaluated topical nisin for treating staphylococcal mastitis in nursing mothers, reporting complete resolution of clinical symptoms in treated participants by day 14, compared to persistent infection in controls, with no adverse effects observed.^[87] Preclinical studies, including fecal microbiota models as of 2023, have shown that nisin selectively depletes Clostridioides difficile while preserving beneficial bacteria in models of gut infections.^[88] These efforts highlight bacteriocins' role as targeted antimicrobials in topical and gastrointestinal settings, though broader systemic trials are needed. Despite their promise, bacteriocins face key challenges in clinical translation, including poor in vivo stability due to proteolytic degradation, narrow antimicrobial spectra limiting broad utility, and potential immunogenicity from repeated peptide exposure.^[89] To address these, protein engineering strategies such as fusion with stabilizing domains or delivery vehicles—like nisin fused to cell-penetrating peptides—have enhanced bioavailability and spectrum, enabling activity against both Gram-positive and Gram-negative targets in animal models.^[90] Beyond antibacterial uses, bacteriocins show synergies in antiviral and anticancer therapies. Nisin and related lantibiotics inhibit viral replication indirectly by modulating host microbiomes and enhancing immune responses, with in vitro studies demonstrating synergy with antivirals against enveloped viruses like HIV and influenza through membrane disruption.^[91] In cancer, bacteriocins such as nisin induce apoptosis in tumor cells (e.g., leukemia and breast cancer lines).^[92] These multifaceted effects underscore bacteriocins' potential as adjuvants in multimodal therapies.

Research and Resources

Emerging Research Directions

Recent advancements in bacteriocin research since 2020 have leveraged artificial intelligence and machine learning for in silico prediction of novel bacteriocins, enhancing discovery efficiency. Tools like BAGEL4, updated to include expanded databases of ribosomally synthesized and post-translationally modified peptides (RiPPs), have enabled comprehensive genome mining by identifying structural genes, immunity proteins, and transport mechanisms in bacterial operons.^[93] For instance, a 2024 analysis of urobiome isolates using BAGEL4 identified 80 putative bacteriocin gene clusters, including 53 novel variants across classes I, II, and III, demonstrating its utility in uncovering diverse antimicrobial peptides from understudied microbiomes.^[93] Concurrently, studies on Actinomycetota producers have revealed significant untapped potential; a 2024 investigation mined 430 genomes to discover 757 aureocin A53-like leaderless bacteriocins, with 97 from Actinomycetota, leading to the synthesis and validation of two novel peptides, arcanocin and arachnicin, active against Lactococcus lactis.^[94] These findings underscore Actinomycetota's role as a prolific source of leaderless bacteriocins, particularly from human gut and oral microbiomes, addressing gaps in phylum-specific diversity.^[94] In synthetic biology, efforts to engineer broad-spectrum bacteriocin variants have advanced through modular genetic circuits and cell-free expression systems. A 2025 study utilized synthetic biology principles—such as abstraction and standardization—to develop multiplexed bacteriocin synthesis platforms, producing cocktails of peptides like microcin V for targeted antimicrobial activity against multidrug-resistant pathogens.^[95] Complementing this, CRISPR-based strategies have activated silent gene clusters encoding bacteriocins by rewiring endogenous regulation. For example, CRISPR interference and activation (CRISPRi/a) tools inserted synthetic promoters into silent biosynthetic gene clusters (BGCs) in Streptomyces species, yielding significantly increased production of secondary metabolites from silent BGCs, without off-target effects.^[96] These approaches facilitate the unlocking of cryptic bacteriocin pathways in Actinomycetota and other producers, expanding the repertoire of engineered antimicrobials. Clinical translation of bacteriocins faces significant gaps, particularly in systemic applications, with limited human trials due to challenges like proteolytic instability, potential immunogenicity, and insufficient toxicity data from preclinical models.^[97] Only a handful of trials, such as those evaluating nisin for ventilator-associated pneumonia (NCT02928042), have progressed beyond animal studies, highlighting the need for more robust pharmacokinetic and safety assessments.^[97] Research has shifted toward combination therapies to overcome these hurdles, especially against biofilms; a 2020 formulation combining garvicin KS, micrococcin P1, and penicillin G eradicated methicillin-resistant Staphylococcus aureus (MRSA) biofilms by synergistically reducing viability by over 90% in clinical isolates, outperforming individual components.^[98] Looking ahead, plant-based expression systems offer a promising avenue for scalable bacteriocin production, bypassing microbial fermentation limitations. Transgenic Nicotiana tabacum and Solanum lycopersicum expressing genes for plantaricin, enteriocin, and leucocin yielded active peptides that inhibited plant pathogens like Clavibacter michiganensis and Pseudomonas syringae, with stable inheritance across generations and potential for cost-effective biopesticide manufacturing.^[99] Additionally, bacteriocins may extend to antiviral applications through microbiome modulation; probiotic-derived bacteriocins from Lactobacillus species enhance gut immunity by inhibiting viral replication, such as against influenza and herpesviruses, and restoring microbiota balance, as evidenced by reduced viral loads in preclinical models, though direct clinical efficacy remains unexplored.^[100]

Databases and Computational Tools

Databases and computational tools play a crucial role in the annotation, prediction, and analysis of bacteriocins, enabling researchers to identify novel peptides from genomic and metagenomic data without relying solely on experimental validation. These resources facilitate the mining of bacterial genomes for biosynthetic gene clusters (BGCs) associated with bacteriocin production, support sequence-based searches, and integrate structural and functional annotations to advance discovery in microbiology and biotechnology.^[101] The BAGEL database, specifically its version 4 (BAGEL4), serves as a comprehensive resource primarily for Gram-positive bacteriocins and ribosomally synthesized and post-translationally modified peptides (RiPPs). It includes curated databases of core peptides and hidden Markov model (HMM) motifs for identifying class I and class II bacteriocins, along with tools for genome mining that analyze user-uploaded DNA sequences to detect potential bacteriocin operons. BAGEL4 was released in 2018 and updated by 2023 to expand its core peptide database to approximately 500 RiPPs (class I), 230 unmodified peptides (class II), and additional categories such as lasso peptides and sactipeptides, enhancing its utility for rapid screening of bacterial (meta-)genomes. The tool's web server interface allows visualization of gene clusters and BLAST searches against its databases, making it widely adopted for bacteriocin prospecting.^[101]^[102] BACTIBASE is an open-access database focused on the structural and functional characterization of bacteriocins across all major classes, encompassing both Gram-positive and Gram-negative producers. It provides manually curated annotations for 177 bacteriocins (as of the 2010 second release), including sequence data, physicochemical properties (e.g., molecular weight, isoelectric point), and activity spectra, with tools for sequence alignment and similarity searches to aid in classification and evolutionary studies. Established in 2007 and updated in its second release in 2010, BACTIBASE incorporates experimental data on producer strains, target organisms, and mechanisms, serving as a key platform for comparative analysis and de novo identification. Its emphasis on validated entries distinguishes it from purely predictive tools, supporting detailed functional annotation.^[103]^[104] Other notable resources include AntiSMASH, a versatile platform for detecting BGCs involved in secondary metabolite production, including bacteriocins as RiPPs. AntiSMASH scans genomic sequences using rule-based and HMM-based detection modules to identify clusters encoding lanthipeptides, sactipeptides, and other bacteriocin types, with version 8.0 (released in 2025) introducing enhanced analyses for chemistry, enzymology, and regulation to improve prediction accuracy across bacterial and fungal genomes. Complementing this, the MIBiG repository standardizes information on experimentally characterized BGCs for natural products, including bacteriocins, with version 4.0 (2024) curating over 2,500 entries that link genomic contexts to known bioactivities, facilitating cross-referencing with tools like AntiSMASH for validation. These resources collectively enable high-throughput screening and integration of bacteriocin data into broader natural product pipelines.^[105]^[106] Recent computational advances have introduced machine learning (ML) models for de novo bacteriocin prediction, particularly those integrating metagenomic data to uncover hidden diversity in uncultured microbiomes. For instance, tools like BPAGS (2024) employ feature selection and supervised ML algorithms, such as random forests, trained on BACTIBASE and BAGEL datasets to predict bacteriocin sequences based on physicochemical properties, achieving high precision in identifying novel class II peptides from environmental samples. Similarly, the 2025 study in Cell Genomics utilized meta-omics integration with ML-guided prioritization to predict and synthesize 26 class II bacteriocins from human gut metagenomes, demonstrating the potential of deep learning for scalable discovery in complex microbial communities. These ML approaches, often web-accessible, outperform traditional homology-based methods by handling sequence variability and incorporating metagenomic context, though they require validation against curated databases to minimize false positives.^[107]^[108]

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Aug 19, 2025 · Bacteriocins are underexplored yet promising candidates to combat antimicrobial resistance (AMR) and enable targeted therapy due to their ...
[96]
Activating natural product synthesis using CRISPR interference and ...
We describe a novel approach to activate silent BGCs through rewiring endogenous regulation using synthetic gene regulators based upon CRISPR-Cas.Missing: bacteriocin | Show results with:bacteriocin
[97]
Evaluating the Translational Potential of Bacteriocins as an ... - NIH
Most clinical trials investigating the ability of bacteriocins as an alternative therapy against S. aureus involve nisin. As S. aureus is the predominant ...
[98]
A bacteriocin-based antimicrobial formulation to effectively disrupt ...
Dec 2, 2020 · We show that the combination between garvicin KS, micrococcin P1, and penicillin G potently inhibit cell viability within S. aureus biofilms by causing severe ...
[99]
Plant-produced bacteriocins inhibit plant pathogens and confer ...
Jul 25, 2021 · This study highlights that plants can be used as biofactories for AMP production and that the expression of bacteriocins in planta may offer new opportunities ...
[100]
Probiotic-Based Bacteriocin: Immunity Supplementation Against ...
Jul 26, 2022 · Researchers studied that enhancing the body's immune system by employing probiotic-based bacteriocin helps in fighting against viral diseases ( ...
[101]
BAGEL4: a user-friendly web server to thoroughly mine RiPPs and ...
May 21, 2018 · The bacteriocin database has been updated and now contains almost 500 RiPPs (class 1, see Supplementary Figure S1), 230 unmodified bacteriocins ...
[102]
BADASS: BActeriocin-Diversity ASsessment Software - PMC
Jan 20, 2023 · BAGEL4 was updated and now has about 500 Ribosomally synthesized and post-translationally modified peptides (RiPPs) (class 1), 230 non-modified ...
[103]
BACTIBASE second release: a database and tool platform for ...
Jan 27, 2010 · BACTIBASE is an integrated open-access database designed for the characterization of bacterial antimicrobial peptides, commonly known as bacteriocins.
[104]
BACTIBASE: a new web-accessible database for bacteriocin ...
A new and original database BACTIBASE that contains calculated or predicted physicochemical properties of 123 bacteriocins produced by both Gram-positive and ...
[105]
antiSMASH 8.0: extended gene cluster detection capabilities ... - NIH
Apr 25, 2025 · antiSMASH 8.0: extended gene cluster detection capabilities and analyses of chemistry, enzymology, and regulation
[106]
MIBiG 4.0: advancing biosynthetic gene cluster curation through ...
Dec 9, 2024 · Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard.
[107]
BPAGS: a web application for bacteriocin prediction via feature ...
Jan 9, 2024 · A web application for predicting bacteriocin was created in this study, utilizing a machine learning approach.
[108]
Systematically investigating and identifying bacteriocins in the ...
Sep 2, 2025 · Guided by meta-omics analysis, we synthesized 26 hypothetical bacteriocins from gut commensal species, with 16 showing antibacterial activities.