Introduction

Antimicrobial resistance (AMR) has risen as one of the major public health challenges in recent times. While the discovery of antibiotics revolutionized modern medicine making them the most successful therapeutic agents to be widely used against bacterial infections, the overuse and misuse of antibiotics have resulted in the emergence of antibiotic-resistant bacteria (Alonso et al. 2017; Torres et al. 2018; Baquero et al. 2021). Regardless of the appropriateness of antibiotics use, routine use of antibiotics at the individual and/or community level exerts immense selective pressure which drives bacterial evolution and the development and acquisition of resistant determinants (Bloom et al. 2018; Baquero et al. 2021). Importantly, antibiotic use in human and veterinary medicine and food production is increasing, and this may likely continue into the coming years as unrestrained antibiotic access rises in resource-limited countries (CDC 2018; Hussain et al. 2020; Gupta 2022). The surge and continuous spread of antibiotic-resistant bacteria and the diminished potency of commercially available antimicrobials and therapeutics necessitate a concerted approach to the search for novel and potent antimicrobials that may become alternatives to available antibiotics. Unless the enigma of widespread AMR and associated public health concerns are urgently prioritized and mitigated, global health and economic burdens will continue to worsen.

Over the past decades, there has been growing interest and research exploring several emerging antimicrobial compounds, including antimicrobial peptides, nanomedicines, probiotics, postbiotics, phytochemicals, bacteriophages, etc. as alternatives to antibiotics (Reuben et al. 2019, 2020; Wang et al. 2020a; Mba and Nweze 2022; Anyaegbunam et al. 2022; Field et al. 2023; Ye et al. 2023; Baquero et al. 2024). Interestingly, ribosomally synthesized peptides of bacterial origin have received increased attention and hold great potential as valuable antimicrobial compounds against a broad spectrum of multi-drug resistant (MDR) pathogens as well as therapeutic agents for the treatment of several diseases (Lynch et al. 2019; Magana et al. 2020; Mba and Nweze 2022; Telhig et al. 2022; García-Vela et al. 2023). Bacteriocins, which are antimicrobial peptides synthesized by bacteria have attracted increasing interest due to their high antimicrobial activities, stability, and low toxicity (Cotter et al. 2013; Lynch et al. 2019; Deslouches et al. 2020; Wiman et al. 2023). The majority of bacteria synthesize at least one known or unknown bacteriocin (Riley and Wertz 2002; Meade et al. 2020; Darbandi et al. 2022). While the ecological function of bacteriocins is yet to be fully elucidated, they are believed to help bacteria outcompete other members of the community, modulate the competitive landscape through direct or exclusive antagonisms, and also serve as signaling molecules (Dobson et al. 2012; Meade et al. 2020; Darbandi et al. 2022).

Bacteriocins are structurally diverse and encoded by highly variable and complex biosynthetic gene clusters that evolve rapidly (Cotter et al. 2013; Heilbronner et al. 2021; Ye et al. 2023). The high antimicrobial activity, diversity, low toxicity, stability, and therapeutic benefits of bacteriocins have prompted a soaring multi-sectorial and transdisciplinary interest in their search, characterization, and broad applications either as (i) antimicrobial/therapeutic compounds for the treatment and prevention of human and animal diseases, (ii) food additives for the inhibition of foodborne pathogens or spoilage organisms, (iii) feed supplements for growth promotion in animal production, or (iv) microbiome-based interventions for the modulation of the gut, reproductive tract, respiratory tract, skin, and food microbiomes (Cotter et al. 2013; Jayaraman et al. 2013; Campion et al. 2013; Vieco-Saiz et al. 2019; Sarika et al. 2019; Liu et al. 2020; Soltani et al. 2021a; Bosák et al. 2021; Saur et al. 2021; Polak et al. 2021). Bacteriocins have a high potential for medico- and techno-economic use in biomedicine and agri-food systems, thus depicting their relevance and prospects across the One Health continuum.

From a cross-disciplinary and multisectoral perspective, several bacteriocins from both Gram-negative and Gram-positive bacteria are being explored. Some of these bacteriocins have shown great potential and prospects for field applications. Bacteriocin research has evolved from basic characterization to high-throughput identification and applications in multiple systems. The increasingly comprehensive scientific reports of multi-sourced (and novel) bacteriocins as well as their impacts on human and animal health, food quality and safety, [micro]ecological landscapes, and industry necessitate their unified compilation and synthesis. Furthermore, bacteriocin research and bibliographies are often disjointed in a ‘stand-alone’ manner seldom without a nexus linking them across disciplines. Understanding the current bacteriocin research across disciplines will inform concerted future research direction which may further foster interdisciplinary perspectives and collaborations. To this end, this review carefully assessed and compiled significant advances and emerging roles of bacteriocins and related innovations within the One Health continuum. Furthermore, we provided a comprehensive cross-disciplinary, multisectoral, and up-to-date potential and prospects of bacteriocins applications and bibliometrics in the human, animal, and food systems.

Advances in the biology, classification, and sources of bacteriocins

Bacteriocins have been generally defined as ribosomally synthesized antimicrobial peptide molecules that can either be enzymatically modified or remain unaltered (Cotter et al. 2013; Johnson et al. 2018; Simons et al. 2020; Heilbronner et al. 2021). They are abundant and highly diverse with widespread synthesis among different groups of bacteria (Riley and Wertz 2002; Cotter et al. 2013; Fernández-Fernández et al. 2023c). It has been suggested that 30% to 99% of Archaea and bacterial species synthesize one or more bacteriocins (Klaenhammer 1988; Riley 1998). Typically, bacteriocins have a narrow spectrum of bactericidal or bacteriostatic activity against taxonomically related bacteria (O’Connor et al. 2018; Simons et al. 2020; Darbandi et al. 2022), but occasionally they can have a broad spectrum of activity against unrelated bacteria (Cotter et al. 2005; Mills et al. 2011; Silva et al. 2018). The biosynthetic mechanisms for these antimicrobial peptides are relatively simple and often encoded in transferable elements such as plasmids and transposons (Klaenhammer 1993; And and Hoover 2003; Fernández-Fernández et al. 2023b). Bacteriocins are synthesized as biologically inactive precursor peptides harboring an N-terminal leader sequence (Kanmani et al. 2013; Liu et al. 2023). These precursor peptides are often detached from the leader peptide and exported outside the cell after post-translational modifications (PTMs) (Riley and Wertz 2002; Mokoena 2017; Soltani et al. 2021a). Bacteriocinogenic bacteria have developed mechanisms to protect themselves from being killed by the bacteriocins they produce. These mechanisms include using efflux pumps to export bacteriocins from inside the cells to the outside, synthesizing self-immunity proteins, or using both mechanisms in some instances (Bastos et al. 2015; Ben Lagha et al. 2017; Bountra et al. 2017).

The function of bacteriocins depends on the recognition of specific receptors and ionic interactions with the hydrophobic surface molecules of target cells (Soliman et al. 2010; Todorov et al. 2022; Śmiałek-Bartyzel et al. 2023). This is typically considered the initial step of the antimicrobial mechanism of action exerted by bacteriocins. To infiltrate the cell membrane and compromise cellular integrity, bacteriocins must effectively recognize these receptors and also express physicochemical interactions with the target cells. For example, receptors like mannose phosphotransferase and lipid II are primarily recognized by class II, unmodified bacteriocins (such as pediocin PA-1 and enterocin CRL35) and class I, post-translationally modified bacteriocins (RiPPs) (such as nisin and mutacin 1140), respectively (Grein et al. 2019; Wang et al. 2020c; Zhu et al. 2022). These intricate interactions between bacteriocins and target cells are often influenced by various physicochemical factors such as temperature, pH, and other chemical constituents. These factors also affect cell membrane integrity and physiological conditions, which consequently impact bacteriocin interactions with specific receptors or directly with the cell membrane (Todorov et al. 2022). Depending on their primary structure and complexity, bacteriocins exert antimicrobial activity through distinct mechanisms of action on susceptible microbial strains. Some bacteriocins cause cell lysis by inhibiting cell wall synthesis or forming pores in the cell membrane. Others act inside the target cells, inhibiting protein production and gene expression (Dobson et al. 2012; Darbandi et al. 2022).

Since the discovery of bacteriocins about a century ago, there has been an increasing number of characterized and identified bacteriocins. These bacteriocins are heterogeneous and highly diverse, possessing a wide range of complexities, structures, sizes, mechanisms of action, spectra of activity, and target cells. To better collate and understand the structural and functional diversities of bacteriocins, some integrated open-access databases and tools have been developed. These include antiSMASH 2.0 [http://antismash.secondarymetabolites.org/ (Blin et al. 2013)], BAGEL3 [http://bagel.molgenrug.nl/ (van Heel et al. 2013)], ADAM, [http://bioinformatics.cs.ntou.edu.tw/ADAM (Lee et al. 2015)], BACTIBASE, [http://bactibase.hammamilab.org (Soltani et al. 2021a)], NucleBact [https://pubmlst.org/projects/nuclebact (Sharp et al. 2017)], LABiocin [https://bio.tools/LABiocin_database (Kassaa et al. 2019)], BUR—bacteriocins database URMITE [https://drissifatima.wixsite.com/bacteriocins (Drissi et al. 2015)], Bacteriocin (https://aapep.bocsci.com/), and Syngulon (https://syngulon.com/). Following the first bacteriocin classification by Klaenhammer (1993), several classifications have been proposed and used in recent years. Due to the advent of cutting-edge high throughput technologies and new developments in bacteriocins’ structures, functions, and mechanisms of action, the classification of bacteriocins progressively evolved, undergoing continuous modification. These classification systems primarily hinge on multiple factors such as physical properties, chemical structure, molecular composition, size, stability, mechanism of action, post-translational modification, microbial target, organism producing them, and cell wall type (Klaenhammer 1993; Dobson et al. 2012; Arnison et al. 2013; Cotter et al. 2013; Bastos et al. 2015; Alvarez-Sieiro et al. 2016; Johnson et al. 2018; Soltani et al. 2021a).

Building on the previous classification (Cotter et al. 2013) and recent advances in ribosomally synthesized and post-translationally modified peptides (RiPPs), the latest and updated classification system proposed by Soltani et al. (2021a) suggests two large classes of bacteriocins. Class I, also referred to as RiPPs have molecular masses < 5 kDa and contain post-translational modifications (PTMs). Class I is subdivided into 12 subclasses, including lanthipeptides, sactipeptides, linear azole(ine)-containing peptides (LAP), circular peptides, glycocins, nucleotide peptides, lasso peptides, siderophore peptides, and Bottromycins from both Gram-positive and Gram-negative bacteria (Cotter et al. 2013; Norris and Patchett 2016; Mills et al. 2017). Additionally, thiopeptides and linaridins from Actinobacteria (Bagley et al. 2005; Claesen and Bibb 2010), and cyanobactins produced by different cyanobacteria (Martins and Vasconcelos 2015; Martins et al. 2018) are subclasses of class I bacteriocin. Class II bacteriocins, also known as unmodified bacteriocins, have molecular masses < 10 kDa and are subdivided into three subclasses: pediocin-like bacteriocins (single peptides containing the YGNGV consensus sequence), two peptides bacteriocins (containing two or more unmodified peptides), and non-pediocin-like bacteriocins (unmodified linear single peptides devoid of the YGNGV) (Mills et al. 2017; Soltani et al. 2021a) (Fig. 1). Generally, the PTMs make class I bacteriocins more stable to extreme pHs, high temperatures, or proteolysis than class II bacteriocins. However, the presence of disulfide bridges in class II bacteriocins relatively increases their stability (Soltani et al. 2021a).

Fig. 1
figure 1

Updated classification of bacteriocins based on post-translationally modified and unmodified peptides (Adopted from Mills et al. 2017; Soltani et al. 2021a)

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Bacteriocins are abundant and heterogeneous in nature. Bacteriocin-producing bacteria can be found in both conventional and unconventional sources. While the human gut is considered a conventional source of bacteriocinogenic bacteria, unconventional sources include soil, water, foods/food products, animal guts, and the vagina and nose of animals and humans (Ryan et al. 2008; Vera Pingitore et al. 2009; Lo Verso et al. 2018; Zielińska and Kolożyn-Krajewska 2018; Fuochi et al. 2019; Reuben et al. 2020; Darbandi et al. 2022; Fernández-Fernández et al. 2023a, b, c, d; Navarro et al. 2023). Common bacteriocin-producing bacteria in humans include Enterococcus, Escherichia coli, Lactobacillus, Lactococcus, Pediococcus, Staphylococcus, and Streptococcus (Ryan et al. 2008; Lakshminarayanan et al. 2013; Zalewska et al. 2018; Laux et al. 2019; Kassem et al. 2021; Darbandi et al. 2022). These bacteria not only act as the first line of defense against invading pathogens, but their bacteriocins also play a role in enhancing the immune system (Zipperer et al. 2016; O’Sullivan et al. 2019).

Interestingly, most of the bacteriocins that have been successfully characterized and identified are produced by lactic acid bacteria (LAB), which are frequently found in milk and dairy products. LAB is a diverse group of bacteria that has garnered significant interest due to their widely recognized safety status, known as ‘Generally Recognized as Safe’ (GRAS) and ‘Qualified Presumption of Safety’ (QPS) status (Reuben et al. 2020; Zimina et al. 2020). Some well-known bacteriocinogenic bacteria commonly found in dairy products include Lactococcus lactis and Lactobacillus plantarum (found in camel, cow, and goat milk), Lactobacillus kefiranofaciens and L. plantarum (found in cheese and kefir), and Lactobacillus brevis, Enterococcus spp., and Streptococcus thermophilus (found in other dairy products) (Reuben et al. 2020; Zimina et al. 2020; Benkirane et al. 2022). Lactobacillus acidophilus is commonly isolated from yogurt and fermented soy products as a bacteriocin-producing bacterium, while Bifidobacterium lactis and Brevibacillus brevis are most commonly found in raw milk (Darbandi et al. 2022). In milk products, Lactobacillus, Lactococcus, and Streptococcus are the predominant bacteriocin-producing bacteria.

From fermented raw or cooked meat products, Lactobacillus brevis, Lactobacillus curvatus, Lactobacillus fermentum, Lactobacillus plantarum subsp. plantarum, Enterococcus faecium UAM1, Pediococcus pentosaceus, and P. accidilactici are widely isolated bacteriocinogenic bacteria (Aymerich et al. 2011; Zielińska and Kolożyn-Krajewska 2018; Khorshidian et al. 2021; García-López et al. 2023; Kaveh et al. 2023). These bacteria exhibit inhibitory activity against major foodborne pathogens including Aeromonas hydrophila, Listeria monocytogenes, and Staphylococcus aureus, thereby preventing their growth in meat products (Winkowski and Montville 1992; Khan et al. 2016). E. faecium HL7, L. plantarum, and L. brevis LAP2 are commonly associated with fish and seafood (Vijayabaskar and Somasundaram 2008; Gómez-Sala et al. 2015; Ringø et al. 2018), while L. brevis, L. paracasei, L. pentosus, L. fermentum, L. plantarum, Weissella, Pediococcus, and Enterococcus durans are known bacteriocin-producing bacteria found in fruits and vegetables (Knorr 1998; Linares-Morales et al. 2020). Soil is another extensively studied unconventional source of bacteriocinogenic bacteria. Many bacteriocins obtained from soilborne bacteria and rhizosphere exhibit inhibitory and biocidal activity against phytopathogens, pests, and insects, making them useful for plant protection as well as biopesticides, bioinsecticides, and growth stimulants (Lv et al. 2017; Zimina et al. 2020). Soil bacteria, including Pseudomonas putida BW11M1, Bacillus subtilis 14B, and Clavibacter michiganensis subsp. michiganensis (Cmm) produce bacteriocin putidacin, Bac 14B, and michiganin A which have inhibitory activity against P. putida GR12-2R3, Agrobacter tumefaciens, and C. michiganensis subsp. Sepedonicus, the etiological agents of plant diseases. Similarly, Bacillus clausii GM17 produces bacteriocin Bac GM17 which has broad-spectrum antifungal and antibacterial activity against multiple phytopathogens (Zimina et al. 2020). Recently, our group characterized and identified different bacteriocins of staphylococcal origin from multiple sources including humans, food, migratory birds, pets, wild animals, and the environment (Fernández-Fernández et al. 2022a, b, 2023a; b).

Trends in bacteriocins research: a bibliometrics perspective

To fully comprehend the current direction of bacteriocin research, we conducted a bibliometric analysis to identify the prevalent research trends and gaps in the field as well as future research perspectives. In August 2023, we conducted a comprehensive literature search on the Web of Science core collection database (http://www.webofscience.com/) using the keyword ‘bacteriocin’ to identify relevant bacteriocin-based publications. We included articles published in 16 different languages until August 2023 for our synthesis (Table S1). In total, there were 8303 publications with 270,493 citations recorded in the Web of Science (WoS) core collection between 1958 to August 2023. Throughout this period, we observed a relatively steady increase in the number of articles and citations, with a notable spike in 2021 (articles = 474; citations = 23,638) (Fig. 2). It is worth mentioning that the last decade has seen an unprecedented exponential increase in bacteriocin-related research, nearly doubling the total research output of previous decades. Given the utilization of advanced technologies in bacteriocin research and the growing global interest and acceptance of bacteriocins in recent years, this trend is not surprising.

Fig. 2
figure 2

Bibliometric indices of bacteriocin-related publications and citations

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There is a wide geographical spread of bacteriocin-related research outputs, spanning 127 countries or regions around the world. The United States, China, and Spain are leading with 1238 (14.907%), 716 (8.621%), and 605 (7.285%) publications respectively, while 26 other countries have over 100 publications each (Table 1). Interestingly, the top regions leading in bacteriocin-related research outputs are North America, Europe, and Asia which are known to have highly industrialized economies. The dominance of these countries can be rationalized by the public perception and national/regional approval of certain bacteriocins for commercial use. For example, the European Union (EU) approved the use of Nisin (E 234) as a food additive in various food categories in the EU under Directive 83/463/EEC, Directive 95/2/EC in 1988, and EU Annex II of Regulation (EC) 1333/2008 in 2006, following its safety evaluation by the European Food Safety Authority expert panel (European Food Safety Authority (EFSA) 2006). Similarly, the Food and Drug Administration of the USA approved the use of nisin as an antimicrobial agent in 1988 (and later amended at 59 FR 14364, Mar. 28, 1994; 68 FR 24879, May 9, 2003; and 88 FR 17724, Mar. 24, 2023) (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=184.1538), and it was given the GRAS status for use in processed food (Cotter et al. 2005; Shin et al. 2016). The periods of these approvals coincided with the rise in antimicrobial resistance to commercially available antimicrobials and concerns about the use of in-fed antimicrobials in livestock production (European Commission 2005).

Table 1 Country-specific bacteriocins-related research outputs (top 50)
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The categorization of publications related to bacteriocins, according to disciplines and specialties demonstrates the broad and multidisciplinary nature of bacteriocin research and applications in various fields, including the One Health systems. Out of the 8303 publications, 45.1% (3749), 30.3% (2513), and 23.6% (1958) were categorized under microbiology, biotechnology and applied microbiology, and food science and technology, respectively. Other disciplines that have significant bacteriocin-related research outputs, with over 100 publications, include pharmacology and pharmacy, biochemistry and molecular biology, agriculture, infectious diseases, immunology, nutrition and dietetics, plant sciences, chemistry, veterinary sciences, dentistry and oral medicine, and multidisciplinary sciences (Fig. 3). Microbiology is the discipline with the highest number of research outputs, which is expected since bacteriocins are microbial products. Therefore, most microbiological research focuses on characterizing, synthesizing, and identifying (novel) bacteriocins from various microorganisms isolated from both conventional and unconventional sources. Biotechnology and applied microbiology, as well as food science and technology, are also prominent research areas in bacteriocins-related publications, highlighting the dynamic and diverse biotechnological applications of bacteriocins and their increasing use in food production (Gharsallaoui et al. 2016; Chandrakasan et al. 2019). Furthermore, emerging areas with bacteriocin-related publications include obstetrics and gynecology, dermatology, oncology, soil science, nanoscience and nanotechnology, neurosciences, entomology, and agronomy. To further support the categorization of bacteriocin-associated research outputs, we examined the intra-discipline citations at both the meso- and micro-scale. Our findings revealed that inflammatory bowel diseases and infections (3325), bacteriology (787), antibiotics and antimicrobials (345), dentistry and oral medicine (236), and plant pathology (187) were the specialized areas with the highest number of citations (Figure S1).

Fig. 3
figure 3

TreeMap representation of bacteriocin-related publications across disciplines

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While Elsevier (1723), Springer Nature (1202), Wiley (914), the American Society for Microbiology (905), and MDPI (323) are the publishers with the most bacteriocin-related publications, the United States Department of Health and Human Services (HHS), the National Institutes of Health (NIH), National Natural Science Foundation of China (NSFC), the Brazilian National Council for Scientific and Technological Development (CNPQ), and the Spanish Government are among the leading funding agencies for bacteriocin research (Tables S2 and S3). There is a global spread of funding for bacteriocin research. This demonstrates the willingness of funding agencies across different regions of the world to support bacteriocin research. Finally, among the 17 Sustainable Development Goals (SDGs), 7277, 172, 123, 63, and 46 bacteriocin-related research outputs primarily align with Goal 3: Good Health and Well-being, Goal 2: Zero Hunger, Goal 15: Life on Land, Goal 13: Climate Action, and Goal 12: Responsible Consumption and Production (Table S4). While there are a few bacteriocin research outputs that align with several other SDGs, this highlights the potential of bacteriocins in promoting global peace and prosperity for both people and the planet, both now and in the future (https://sdgs.un.org/goals).

Bacteriocins vs. viable [probiotics/protective cultures] cells: mitigating emerging concerns

Most bacteriocin-producing bacteria, especially (foodborne) LAB and gut commensals are widely used as probiotics or protective cultures in food production and as supplements for animals and humans. Bacteriocin production has long been recognized as an important trait in probiotics or protective cultures (Corr et al. 2007; Dobson et al. 2012; Cotter et al. 2013). Although the exact ecological function of bacteriocins is not fully understood, it is believed that they play a significant role in the functionality of probiotics within their host. Functioning as colonizing peptides, bacteriocins facilitate the colonization and dominance of a producing [probiotic] strain into an already established niche (Riley and Wertz 2002; Anjana 2022). These promising advantages exerted by bacteriocins are attributed to their biofunctional properties and structural diversity (Zhu et al. 2023; Wang et al. 2023). Current research focuses on exploring the underlying bioactivity of bacteriocins in the development of novel probiotics for broad and newer applications in biomedicine and the agri-food industry. Under different conditions, probiotic-derived bacteriocins are often evaluated and used alone or in combination with the producing strains (Umair et al. 2022; Hussien et al. 2022; Ahn et al. 2023; Mihailovskaya et al. 2023; Yu et al. 2023). Bacteriocins can directly inhibit pathogens and other competing microorganisms (Majeed et al. 2011; Simons et al. 2020) or modulate the composition and diversity of microbial communities and the host immune system through signaling mechanisms (Czárán et al. 2002; Di Cagno et al. 2007; Chikindas et al. 2018). For example, vancomycin-resistant enterococci (VRE) were successfully controlled using pediocin PA-1-producing P. acidilactici MM33. Conversely, no effect was recorded using the non-pediocin PA-1 producing P. acidilactici MM33 strain (Millette et al. 2008). In separate studies, novel bacteriocins such as cerein B4080, cerein 7B, bacteriocin AS-48, garvicin KS, and micrococcin P1 were studied and proposed as promising alternatives for the treatment of skin and soft tissue infections caused by multidrug-resistant Staphylococcus aureus (Ovchinnikov et al. 2020; Velázquez-Suárez et al. 2021; Jaumaux et al. 2023). Like probiotics, the antimicrobial properties of bacteriocins are pathogen-specific and activity-dependent (Tran et al. 2023; Zhu et al. 2023). Similarly, oral administration of bacteriocin (ABP118) producing L. salivarius UCC118 reportedly controlled L. monocytogenes infection than the non-ABP118 producing strain of L. salivarius UCC118 (Corr et al. 2007). Therefore, assessing the antimicrobial profiles of bacteriocins against multiple pathogens under different conditions is a prerequisite for their selection in the treatment of antibiotic-resistant pathogens in clinical settings.

The common and primary denominator in probiotics and protective cultures is the viability of the cells. Both probiotics and protective cultures essentially consist of live or viable cells specifically selected to confer desired benefits when used in adequate amounts (Hill et al. 2014; Hammami et al. 2019; Fischer and Titgemeyer 2023). However, emerging evidence demonstrates their viability as a non-essential precursor for exerting the desired beneficial properties. Some non-viable components from probiotics and protective cultures, such as bacteriocins and postbiotics, can exude comparable beneficial properties (Raman et al. 2016; Hammami et al. 2019; Homayouni Rad et al. 2021; Mack et al. 2022; Liang and Xing 2023; Teng et al. 2023). Bacteriocins are highly diverse and often outperform viable cells in terms of safety, bioavailability, absorption, distribution, and metabolism while maintaining cognate bioactivities (Ng et al. 2020; Todorov et al. 2022; Liang and Xing 2023).

In recent decades, there have been overwhelming concerns associated with the use of probiotics and protective cultures, particularly regarding the acquisition and distribution of undesired genes, such as antibiotic resistance and virulence. In most cases, microbial strains used as probiotics or protective cultures are generally benign and pose no risk. However, untoward conditions, especially horizontal transfer directly or indirectly predispose them to acquire or spread antibiotic resistance and virulence genes among the commensal microbiota (and opportunistic pathogens) inhabiting the same niche (Imperial and Ibana 2016; Costa et al. 2018; Kothari et al. 2019). Human or animal microbiota is believed to be a trove of numerous [functional] genes, including antibiotic resistance genes which can be easily shared or transferred between resident and transient bacteria (e.g., probiotics and pathogens) (Kothari et al. 2019). Several studies have extensively documented the transfer of undesirable genes between the resident microbiota (in the gut or food) and the strains used as probiotics or protective cultures (Hu et al. 2013; Aarts and Margolles 2014; Abriouel et al. 2015; Wolfe 2023; Sada et al. 2024). Other concerns associated with the use of probiotics and protective cultures include deleterious metabolic activities and imbalances, the eruption of excessive immune responses, persistent microbial colonization that disrupts the normal microbiota, septicemia, and localized or systemic infections (Spano et al. 2010; Doron and Snydman 2015; Pararajasingam and Uwagwu 2017; Costa et al. 2018; Kim et al. 2018; Sada et al. 2024).

The concerns associated with the use of live cells necessitate the use of bacteriocins, which may be safer for application in multiple systems. Since most microbial strains used as probiotics or protective cultures produce known (or unknown) bacteriocins or bacteriocin-like inhibitory substances (BLIS) that exert similar beneficial effects as the viable strains, it is believed that researchers may sooner than expected preferably explore the use of bacteriocins to mitigate the concerns associated with the use of viable cells. Bacteriocins seem to pose little or no risks for use within animal, human, and food systems while exerting their heterogeneous beneficial effects. Therefore, they may be the most preferred choice for broad applications earlier than anticipated. To fully understand the risks associated with the use of viable cells and to establish the preference for bacteriocin applications in real-life situations, more comprehensive studies using experimental evolution across multiple systems are required.

Applications of bacteriocins

As the science of bacteriocins steadily progresses, their areas of application are increasing proportionately, encompassing previously unknown areas. Since their discovery, bacteriocins have been used to improve food production, preservation, and safety in the food industry. However, their potential has now extended to various fields, including biotechnology, ecology, pharmaceuticals, agriculture, clinical settings, and veterinary medicine. Bacteriocins offer sustainable solutions to a wide range of scientific problems. Here, we critically evaluated and compiled the significant advances and emerging roles of bacteriocins as well as the latest bacteriocin-related innovations aimed at harnessing their heterogeneous potential and prospects for multisectoral applications in health and agrifood systems. Table 2 summarizes some bacteriocins with potential applications in different systems.

Table 2 Bacteriocins with potential applications
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Modulation of microbiomes

The microbiota is crucial and necessary for maintaining homeostasis, the host defense system, disease prevention, and overall health and well-being. The composition and diversity of the microbiota vary depending on localized regions (e.g., oral, nasal, respiratory, gut, and skin) and consist of highly diverse and complex communities with specialized autochthonous bacteria (Berg et al. 2020; Anjana 2022; Baquero et al. 2019; Zheng et al. 2023; Ormaasen et al. 2023; Reuben et al. 2023; Pérez-Cobas et al. 2023; Ferraz 2023). Dysbiosis of the microbiota often leads to physiological dysfunction, dysregulation, and diseases (Hou et al. 2022). Numerous studies have highlighted the indiscriminate impact of antibiotics on the microbiota, resulting in dysbiosis and perturbations of microbial composition and diversity that predispose the host to metabolic and immune system disorders (Francino 2015; Sanchez-Rodriguez et al. 2020; Hou et al. 2022). Unlike antibiotics, bacteriocins have a narrow spectrum of activity, are highly specific, and can inhibit pathogens without disrupting host-microbiota homeostasis or causing detrimental effects. Bacteriocins that can promote beneficial shifts in the abundance, composition, and diversity of the microbiota may provide sustainable and valuable microbiome-based solutions for the treatment of infectious and non-infectious microbiome-related diseases resulting from microbiota dysbiosis.

Furthermore, bacteriocin production by most bacteria can be seen as a strategy to modulate the microbiome (Pu et al. 2022; O’Reilly et al. 2023; Ríos Colombo et al. 2023; Rani and Tiwari 2023; Puls et al. 2024). Bacteriocins can either prevent invasion by allochthonous bacteria (competitors or pathogens) or stimulate the immune system to prevent oxidative stress and inflammation (Dahiya et al. 2017; Bäuerl et al. 2017; Heilbronner et al. 2021; Rani and Tiwari 2023; Puls et al. 2024). In another instance, bacteriocin-producing bacteria can invade and colonize communities predominantly populated by susceptible strains (Riley and Gordon 1999; Heilbronner et al. 2021). Bacterial interactions within the microbiota are characterized by both competition (antagonism) and cooperation (mutualism), which require a delicate balance for overall microbiota functioning and cohesion (Heilbronner et al. 2021; Pérez-Cobas et al. 2023). However, the mechanisms regulating the integration and modulation of bacteriocins in this complex multifactorial meshwork remain a black box.

Although the roles of bacteriocins in microbiome modulation and the maintenance of homeostasis and host health are limited, extensive metagenomic analysis substantially revealed the omnipresence of bacteriocin biosynthetic gene clusters across human microbiomes (Donia et al. 2014; Aleti et al. 2019; Naimi et al. 2022). In a study, several bacteriocins, including garvicin ML (GarML), plantaricins EF and JK (plantaricins), enterocins P, Q, and L50 (enterocins), pediocin PA-1 (PedPA-1), and sakacin A (SakA) were reported to beneficially modulate the gut microbiota in mice (Umu et al. 2016). While these bacteriocins differ greatly in terms of physicochemical properties and inhibition spectrum, their administration had a favorable impact on the microbiota, resulting in changes at the taxonomic level, increased abundance of LAB, and a decrease in Enterococcaceae, clostridia, and staphylococci. Recent studies showed that nisin, lacticin 3147, pediocin PA1, and bactofencin A separately modulated gut microbiota, resulting in subtle and beneficial alterations in pigs, Simplified Human Intestinal Microbiota (SIHUMI), and simulated colon models (Ríos Colombo et al. 2023; O’Reilly et al. 2023; Pu et al. 2022; Guinane et al. 2016). Bactofencin A increased the relative abundances of Bifidobacterium and Streptococcus while lowering the abundances of Blautia and Clostridium spp. (Arboleya et al. 2016; Sun et al. 2020). Bifidobacterium spp. are considered important microbes in healthy microbiota and are associated with probiotic properties. Mice fed with bacteriocin-producing L. salivarius UCC118 for eight weeks showed changes in gut microbiota compared to those fed with non-bacteriocin-producing variants (Murphy et al. 2013). Treatment with bacteriocin-producing L. salivarius UCC118 significantly increased Proteobacteria and Bacteroides while decreasing Actinobacteria. Similarly, the assessment of L. salivarius bacteriocin, bactofencin A, in a simulated gut microbiota system showed significant microbiota modulation in both the bactofencin A-producing strain and bactofencin A treatments compared with the non-bactofencin A producing mutant (Guinane et al. 2016). Bacteriocin production subtly changes the community structure of the gut microbiota at the taxonomic level, maintaining a beneficial and desirable microbiota (Guinane et al. 2016; Garcia-Gutierrez et al. 2019; O’Connor et al. 2020). In the same manner, Naimi et al. (2022) recently reported the subtle beneficial modulatory effect of Microcin J25 (MccJ25) or reuterin on the overall colon microbiota diversity and metabolome of swine.

Within the oral cavity, some strains of S. mutans produce bacteriocins called mutacins which modulate the oral microbiome by inhibiting phylogenetically related plaque-forming strains (Gillor et al. 2008). There is a positive correlation between the production of bacteriocins by S. mutans and their ability to colonize the oral cavity (Hillman et al. 1987, 2000). S. salivarius K12, a commensal of the oral cavity often produces bacteriocins called salivaricins A and B. The presence of S. salivarius K12 which produces salivaricins A and B has been shown to modulate the oral and throat microbiomes, preventing the invasion of oral pathogens such as S. pyogenes and reducing throat infections (Brook 2005; Horz et al. 2007). Similarly, the consumption of milk containing a strain of S. salivarius 20P5, which produces salivaricin A, positively modulates the oral microbiota of children by significantly increasing the production and antagonistic activity of salivaricin A and providing immunity against S. pyogenes infection (Walls et al. 2003). Bacteriocin-producing Lactobacillus spp. including L. gasseri, L. crispatus, L. jensenii, and L. iners, are dominant in the vagina microbiota of healthy women (Vásquez et al. 2002; Pendharkar et al. 2023). In contrast, women with bacterial vaginosis have a distinct vaginal microbiota characterized predominantly by Mycoplasma hominis, Gardnerella vaginalis, Bacteroides, Mobiluncus, Peptostreptococcus, and Prevotella spp., along with lower densities of lactobacilli (O’Brien 2005; Falagas et al. 2007; Turovskiy et al. 2009). The vaginal microbiota is often modulated by bacteriocin-producing lactobacilli, which typically antagonize pathogens, especially G. vaginalis and Candida spp. (Kaewsrichan et al. 2006; Günther et al. 2022).

The skin microbiome consists of a highly diverse array of microorganisms involved in complex but balanced multifactorial interactions with the host and external environment (Carmona-Cruz et al. 2022; Nicholas-Haizelden et al. 2023; Glatthardt et al. 2024). Any imbalance (dysbiosis) in the structure and composition of the skin microbiota often results in skin infections/diseases such as acne, impetigo, atopic dermatitis, and psoriasis (Grice 2014; O’Sullivan et al. 2019; Carmona-Cruz et al. 2022; Richter and Wohlrab 2023; Sato et al. 2023; Puls et al. 2024). Bacteriocins have been used to selectively modulate and restore the skin microbial balance (eubiosis) in situations of dysbiosis caused by pathogen colonization and environmental perturbation (O’Sullivan et al. 2019; Ovchinnikov et al. 2020; Soltani et al. 2022b; Alessandrini et al. 2023; Jaumaux et al. 2023). Lugdunin, a cyclic peptide bacteriocin facilitates the restoration of skin microbial balance while inhibiting different etiological agents of skin infections, especially MRSA and other Gram-positive bacteria (Bitschar et al. 2019; Krauss et al. 2020; Barber and Zhang 2021; Bier and Schittek 2021). Lugdunin is believed to exert microbiome modulatory activity by stimulating the expression of different cutaneous antimicrobial peptides and recruiting phagocytic neutrophils and monocytes (Bitschar et al. 2019; Krauss et al. 2020; Saur et al. 2021; Hirsch et al. 2024). Lugdunin also inhibits colonizing skin pathogens by disrupting the transmembrane pH gradient, which likely leads to protein denaturation and a reduction in proton motive force, obstructing cellular respiration (Krulwich et al. 2011; Farha et al. 2013; Barber and Zhang 2021). Similarly, two recently discovered bacteriocins, cerein B4080 and cerein 7B, reportedly enhance skin microbiome eubiosis by selectively promoting the growth of skin commensals while inhibiting pathogens (Jaumaux et al. 2023). By preserving skin commensals through competitive exclusion/inhibition of pathogens, bacteriocins could beneficially modulate the skin microbiome while limiting the emergence and spread of superbugs within the skin ecosystem, thereby reducing skin infections (Meade et al. 2020; Soltani et al. 2022b; Jaumaux et al. 2023). Other bacteriocins that show high potential for application in skin microbiome modulation include garvicin KS, nisin Z, bactofencin A, pediocin PA-1, subtilosin, microcin J25, micrococcin P1, subtilin, bacteriocin A37, and reuterin (Joseph et al. 2013; O’Sullivan et al. 2019; Ovchinnikov et al. 2020; Heilbronner et al. 2021; Soltani et al. 2022b; Alessandrini et al. 2023; Puls et al. 2024). There is a need to further explore the mechanisms of activity and pharmacological benefits of promising skin-relevant bacteriocins for their suitability in clinical application and commercialization.

Bacteriocins have also been used to modulate food microbiota to improve organoleptic properties, quality, and microbiological safety. The growing knowledge of the structure and function of food microbiota now influences their modulation towards desirable functions and beneficial outcomes. Food microbiota are often modulated through the regulation of abiotic factors or by using specific microorganisms and/or their products, such as bacteriocins (And and Hoover 2003; Walsh et al. 2023). The latter involves the use of various forms of bacteriocins, whether purified or semi-purified, and/or bacteriocin-producing strains to modulate food microbiota (O’Sullivan et al. 2003; Ramu et al. 2015; Silva et al. 2018). It has been demonstrated that the microbiota of fermented foods (e.g., cheese and kefir) can be modulated, making them useful models for shaping food microbiota (Wolfe et al. 2014; Bonham et al. 2017; Wolfe 2018; Blasche et al. 2021; Walsh et al. 2023). The application of bacteriocins or bacteriocin-producing strains as starter or protective cultures in dairy products can confer numerous advantages during food processing. They can modulate the food microbiota by accelerating ripening, as is the case with cheese (Ávila et al. 2005; Martinez et al. 2015), or reduce the growth of adventitious non-starter lactic acid bacteria (NSLAB) and other non-starter microbiota in fermented foods (Oumer et al. 2001; O’Sullivan et al. 2003), or inhibit invasion by environmental or spoilage organisms (Muñoz et al. 2004, 2007), or significantly reduce the growth of foodborne pathogens (Carnio et al. 2000; Aspri et al. 2017; Kondrotiene et al. 2018), or accelerate enzyme release and activities (O’Sullivan et al. 2003), or enhance fermentation (Oumer et al. 2001). Additionally, bacteriocin production has been detected in LAB bacteria recovered from wine during malolactic fermentation, especially among L. plantarum strains (Navarro et al. 2000; Rojo-Bezares et al. 2008; Díez et al. 2012). During vinification, bacteriocin production could be an important characteristic to consider when selecting LAB as starters for malolactic fermentation. Furthermore, bacteriocins produced by LAB have significant potential for use as biocontrol agents against foodborne and spoilage organisms as well as biopreservatives throughout the enological processes (Díez et al. 2012; Dündar 2016; Fernández-Pérez et al. 2018).

Medical and pharmaceutical applications

The emergence and spread of infectious diseases, especially those caused by antimicrobial-resistant pathogens, and the increasing morbidity and mortality due to non-communicable diseases like diabetes and cancer pose major threats to global health (PAHO/WHO 2019; WHO 2021). Due to their high antimicrobial activity against a wide range of pathogens, safety, biocompatibility, unique mechanisms of action, biodegradability, high specificity, and nanomolar range, bacteriocins exert desirable heterogeneous traits relevant for medical application (Naveen and Kalaivani 2018; Meade et al. 2020; Le et al. 2021, 2023; Reinseth et al. 2024; Rossi et al. 2024). The potential of bacteriocins in medicine has been demonstrated through various in vitro, ex vivo, and in vivo experiments, with some undergoing clinical evaluation. However, concerns have risen regarding solubility, stability, bioavailability, sensitivity to proteolytic enzymes, high cost, and the challenges of large-scale purification and production for general use, which often limit the direct use of bacteriocins in clinical studies and hinder their industrial production and commercialization (Böttger et al. 2017; Mathur et al. 2018; Hols et al. 2019; Soltani et al. 2021a). Nevertheless, due to the unique and diverse medical potentials exhibited by bacteriocins, further investigations involving cutting-edge bioengineering techniques can be conducted to address these concerns and improve their properties and large-scale production for general medical use.

Inhibition of pathogens: viable alternatives to antibiotics

Since the discovery of antibiotics, they have played a significant role in the prevention and treatment of animal and human diseases. However, the emergence and increasing spread of multi- and extensive-drug-resistant superbugs necessitate the urgent use of novel, suitable, and sustainable strategies for infection control, treatment, and addressing AMR concerns. Bacteriocins show great promise as sustainable alternatives to currently available antibiotics. Numerous studies have described the unique mechanisms of action and potency of different bacteriocins against a broad range of superbugs (Bastos et al. 2009, 2015; Svetoch et al. 2009; Ahmad et al. 2017; Goodarzi et al. 2020; Ovchinnikov et al. 2021; Benítez-Chao et al. 2021; Sharma et al. 2022; Soltani et al. 2022a; Barman et al. 2023; Ghapanvari et al. 2022; Bahy et al. 2023; Ibraheim et al. 2023; Wolden et al. 2023; Reinseth et al. 2024). Over the years, many studies have reported the antimicrobial properties of various bacteriocins against clinically important pathogens responsible for respiratory tract, nosocomial, dental, skin, and gastrointestinal tract infections. Bacteriocins have also been shown to have inhibitory effects on multidrug-resistant pathogens including C. difficile, vancomycin-resistant Enterococcus (VRE), methicillin-resistant S. aureus (MRSA), Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenza, Listeria spp., Salmonella spp., Enterobacter spp., Acinetobacter spp. and others (Oman and van der Donk 2009; Lay et al. 2016; Hanchi et al. 2017; Yu et al. 2019; Velázquez-Suárez et al. 2021; Ghapanvari et al. 2022; Bahy et al. 2023; Le et al. 2023; Alattar et al. 2024; Mu et al. 2024; Reinseth et al. 2024). Recently, Ying et al. (2024) and Wolden et al. (2023) separately identified novel bacteriocins, bacteriocin XJS01 and romsacin (produced by Lactobacillus salivarius and Staphylococcus haemolyticus) which showed broad-spectrum activity against Gram-positive World Health Organization (WHO) priority pathogens such as VRE (E. faecium) and MRSA. Additionally, romsacin also eradicated the biofilms of VRE, MRSA, Staphylococcus epidermidis, and S. haemolyticus.

Nosocomial infections are mostly caused by MDR E. coli, enterococci, P. aeruginosa, Acinetobacter baumannii, K. pneumoniae, pneumococci, S. aureus, and Proteus spp. (Ghodhbane et al. 2015; Khan et al. 2017; Le et al. 2021; Rossi et al. 2024). Lacticin 3147, klebicin, and nisin A have shown high inhibitory activity against multiple nosocomial pathogens including MRSA and VRE (Piper et al. 2009; Ahmad et al. 2017; Alattar et al. 2024; Zhao et al. 2024). These bacteriocins also exhibit significant antagonism against pathogens in the kidney, liver, and spleen. In an in vivo study involving S. aureus Xen 29 infected mice, subcutaneous treatment with lacticin 3147 prevented the systemic spread of the pathogen, indicating the potential of lacticin 3147 as a biotherapeutic in real-life applications (Piper et al. 2009). Pumilicin 4, a bacteriocin produced by Bacillus pumilus, has shown remarkable inhibitory activity against MRSA, VRE, and several Gram-positive bacteria (Aunpad and Na-Bangchang 2007). This demonstrates the potential of the use of Pumilicin 4 in the management of infections caused by MRSA, VRE, and other susceptible Gram-positive pathogenic bacteria. Similarly, planosporicin, a bacteriocin produced by Planomonospora spp. DSM14920, has shown activity against S. pyogenes, S. pneumoniae, and S. aureus (Aunpad and Na-Bangchang 2007). Jabés et al. (2011) and Mota-Meira et al. (2005) separately demonstrated high in vitro and in vivo inhibitory activities of bacteriocins NAI-107, mutacin B-Ny266, and microbisporicin against MDR pathogens. Additionally, the activity of microcin J25, a bacteriocin produced by E. coli against multidrug-resistant Enterobacteriaceae has also been reported (Telhig et al. 2022).

The growth of major pathogenic bacteria including H. influenzae, Pasteurella multocida, Mycobacterium tuberculosis, P. aeruginosa, or Moraxella catarrhalis, responsible for various respiratory tract infections (RTIs) such as rhinitis, pneumonia, otitis, and tuberculosis were reportedly inhibited by different bacteriocins (mutacin B-Ny266, bacteriocin L23, lantibiotic MU1140, nisin F, and Mersacidin) under in vivo conditions in mice and Wistar Rats models and in vitro models (Kruszewska et al. 2004; Mota-Meira et al. 2005; Pascual et al. 2008; De Kwaadsteniet et al. 2009; Ghobrial et al. 2009; Le et al. 2023; Martin et al. 2023; Zhao et al. 2024). The activities of these bacteriocins under varied in vivo conditions, including immunosuppression, were observed to have no toxicity to the bronchi, trachea, lungs, or haematology of the evaluated animals. Similarly, purified salivaricin D and mutacin 1140 have shown antagonism against known RTI pathogens, P. aeruginosa, S. aureus, and S. pneumoniae (Ghobrial et al. 2009; Birri et al. 2012). Multiple in vitro and in vivo (mice and macrophages) anti-tubercular activities of various bacteriocins (e.g. lacticin 3147, nisin, laterosporulin10, and enterocin AS-48) have been tested against different strains of M. tuberculosis with favorable outcomes (Sosunov et al. 2007; de Kwaadsteniet et al. 2010; Carroll et al. 2010; Aguilar-Pérez et al. 2018). Furthermore, variants of bioengineered nisin S, T, and V tested against M. tuberculosis (H37Ra), M. avium subsp. Paratuberculosis (ATCC 19698), M. avium subsp. Hominissuis (CIT05/03), and M. kansasii (CIT11/06) showed more significant inhibitory activities compared to parent nisin (Carroll et al. 2010). Among the bioengineered nisin variants, nisin S showed the most potent antagonism. Latham et al. (2017) also reported narrow-spectrum activity against nontypeable Haemophilus influenzae (NTHi) by a novel bacteriocin produced by Haemophilus haemolyticus. Their findings suggest that the novel bacteriocin or bacteriocinogenic strains of H. haemolyticus have the potential to reduce NTHi colonization and respiratory tract infection caused by NTHi.

Topical evaluation of bacteriocins has successfully been reported against oral and skin diseases, and breastfeeding women with mastitis (Fernández et al. 2008; Kang et al. 2009; Tong et al. 2014). Etiological agents of these diseases especially Propionibacterium acnes, P. aeruginosa, S. aureus, S. epidermidis, L. monocytogenes, B. subtilis, and B. cereus were controlled using bacteriocins such as nisin, lactocyclicin Q, subpeptin JM4B and hiracin JM79 (Sánchez et al. 2007; Kang et al. 2009; Sawa et al. 2009; Izquierdo et al. 2009; Ovchinnikov et al. 2020; Barman et al. 2023). Similarly, bacteriocins or bacteriocin-based formulas have been topically used for the treatment and prevention of mastitis and intramammary infections in animals Bennett et al. 2021; 2022; Heinzinger et al. 2023; Raheel et al. 2023). Several studies have reported the potency of different bacteriocins against pathogenic bacteria responsible for dental infections, vaginosis, gastric ulcers, gastroenteritis, etc. (Howell et al. 1993; Dover et al. 2007; Miyauchi et al. 2012; Kaewnopparat et al. 2013; van Staden et al. 2016; Cebrián et al. 2019; Ovchinnikov et al. 2020, 2021; Goodarzi et al. 2020; Benítez-Chao et al. 2021; Sharma et al. 2022; Barman et al. 2023; Alessandrini et al. 2023).

Potential antiviral agents

Apart from antibacterial properties exhibited by bacteriocins, several bacteriocins also possess antiviral activities against different viruses. While working with bacteriocins produced by E. faecium CRL35, (Wachsman et al. 1999) first described the antiviral activity of enterocin CRL35 against Herpes simplex viruses (HSV-1 and HSV-2). Enterocin CRL35 interferes with intracellular viral multiplication and inhibits viral late stages of replication (Wachsman et al. 2003; Al Kassaa et al. 2014). Similarly, enterocin ST4V and enterocin ST5Ha produced by E. mundtii ST4V and E. faecium ST5Ha, respectively, have shown high potency against HSV-1 and HSV-2 (Wachsman et al. 2003; Todorov et al. 2005). Bacteriocins produced by L. curvatus and L. delbrueckii subsp. Bulgaricus have shown antiviral properties against murine norovirus (MNV) and influenza virus (H1N1) (Serkedjieva et al. 2000; Lange-Starke et al. 2014). Non-LAB bacteriocins including Subtilosin A, erwiniocin NA4, and staphylococcin 188 produced by B. subtilis, E. carotovora NA4, and S. aureus AB188 independently showed inhibitory activities against HSV-1 (Torres et al. 2013), influenza, Newcastle disease, and coliphage HSA viruses (Qureshi et al. 2006; Saeed et al. 2007), respectively. Likewise, Actinomadura namibiensis DSM 6313 secretes bacteriocin, Labyrinthopeptin A1 (LabyA1) with antiviral activity against HSV and human immunodeficiency virus type 1 (HIV-1) (Férir et al. 2013). LabyA1 inhibited intracellular transmission of HIV-1 between infected and noninfected CD4 + T cells. Lee et al. (2016) similarly demonstrated the antiviral inhibitory activity of Micrococcin P1. In their study, they reported that Micrococcin P1, a naturally occurring macrocyclic peptide efficiently inhibited the attachment, entry, and cell-to-cell transmission of all hepatitis C virus (HCV) genotypes.

In a recent study, bacteriocin-like inhibitory substances produced by E. faecium CM019 isolated from Egyptian dairy products showed broad-spectrum antimicrobial activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and several Gram-positive bacteria activity (Bahy et al. 2023). Generally, the antiviral mechanisms and pharmacodynamics of bacteriocins against viruses are yet to be fully elucidated. However, it is believed that bacteriocins interfere with viral key determinants responsible for viral replication (Wachsman et al. 2003). Further studies are required to decipher the mechanisms of action and pharmacodynamics of bacteriocins against different viruses, especially those emerging with high virulence.

Potential non-invasive bio-diagnostic tool

Emerging reports show the great potential of bacteriocins as valuable tools for bioanalytical purposes in medicine, largely due to their precision, specificity, and in vivo recognition in biological systems. Different studies have demonstrated the labeling of bacteriocins using specific organic probes, fluorescent, or radioactive markers (Imran et al. 2013; Deng et al. 2020; Escobar et al. 2023). Through visualization with fluorescence ratio imaging microscopy, a labeled bacteriocin, fluorescent nisin Z, was able to precisely detect three pathogenic listerial strains: L. monocytogenes CIP 82110, L. ivanovii CIP 12510, and L. innocua CIP 12511 (Imran et al. 2013). Additionally, the mechanism of antilisterial action using the labeled nisin was demonstrated. Technetium-99 m (99mTc)–duramycin a bacteriocin which is known to have high specificity and affinity towards phosphatidylethanolamine was used to identify apoptotic and necrotic cells (Ahmad et al. 2017). The combinatorial use of sodium iodide symporter (NIS) and 99mTc-duramycin single-photon emission computed tomography (SPECT) imaging has proven effective in monitoring the spread of oncolytic virotherapy (OV) and determining the absence or presence of therapeutic-associated cell death (Zhang et al. 2019).

Recent advances in bacteriocin and peptide-based diagnosis, detection, and monitoring of pathogens have been increasingly developed for application in clinical and food systems with remarkable success. Various bacteriocins such as warnericin RK, leucocin, leucocin A, pediocin PA1, and curvacin A, have been used for the detection and monitoring of pathogens including bacteria and viruses, in clinical settings and the food system (Etayash et al. 2014a, b; Azmi et al. 2015; Islam et al. 2021, 2022; Escobar et al. 2023). These advances show the potential application of bacteriocins not only as noninvasive diagnostic tools for the diagnosis and prognosis of both infectious and non-infectious diseases but also for the identification of individuals predisposed to chronic diseases or secondary infections. Additionally, the use of peptide-based biosensors could offer promising, rapid, and highly sensitive alternatives for pathogen detection and food monitoring in agrifood systems.

Potential as anticancer agents

Globally, cancer remains one of the most severe, life-threatening, and difficult-to-treat diseases, resulting from the spread of uncontrollable proliferation of cells. The use of conventional cancer treatments, especially chemotherapy, radiotherapy, and surgery, often results in more devastating side effects and is still unable to curb the rising cases of cancer-associated morbidity and mortality (Naveen and Kalaivani 2018; Meade et al. 2020). A paradigm shift in cancer treatment approaches, including the use of innovative, safe, and sustainable solutions with no severe side effects is imperative. Interestingly, several bacteriocins have demonstrated varying degrees of anticancer activity (Hoskin and Ramamoorthy 2008; Kaur and Kaur 2015; Baindara et al. 2018; Meade et al. 2020). Due to the differences between the membranes of cancerous and healthy cells, bacteriocins can identify and selectively destroy cancer cells (Meade et al. 2020). Unlike healthy cells, which have outer membranes with neutral charged ions, the outer membrane of cancer cells upregulates the expressions of O-glycosylated mucins and phosphatidylserine (Yoon et al. 1996; Dobrzyńska et al. 2005) and becomes negatively charged. The negatively charged cell membranes of cancer cells trigger electrostatic interactions in the presence of [positively charged] bacteriocins (Hammami et al. 2010; Baindara et al. 2018; Meade et al. 2020; Ananou et al. 2020). The inhibitory activity of bacteriocins against cancer cells is primarily based on membrane permeabilization, which is mainly due to the amphiphilic and cationic nature of bacteriocins (Kaur and Kaur 2015; Perez et al. 2018). Ahmadi et al. (2017) reported antiproliferative activity of nisin against colon cancer SW480 cells. Nisin ZP induced anticancer activity, resulting in a high level of apoptosis in squamous cell carcinoma (HNSCC cells) with no histological damage, necrosis, fibrosis, or inflammation even after prolonged exposure to nisin ZP (Kamarajan et al. 2015). Similarly, nisin has shown activity in the control of oral cancer as well as in head and neck squamous cell carcinoma in in vivo mice studies (Lopetuso et al. 2019). Purified colicin, microcin, pediocin, and pyocin have also demonstrated high inhibitory activities in xenograft mouse models and neoplastic cell lines (Shin et al. 2016). Microcin E492, produced by K. pneumoniae, exhibits anticancer properties against breast and colorectal cancer cells through the induction of apoptosis and necrosis in some human cell lines (Hetz et al. 2002).

In recent years, several bacteriocins, including Laterosporulin10, Enterocin 12a, nisin A, Fermenticin HV6b, colicins, and Enterocin LNS18, have shown anticancer properties against various types of cancers in different cancer cell models (Baindara et al. 2017; Norouzi et al. 2018; Al-Madboly et al. 2020; Hosseini et al. 2020; Soleimanpour et al. 2020; Sharma et al. 2021; Balcik-Ercin and Sever 2022; Molujin et al. 2022; Ye et al. 2023). These bacteriocins often exhibit anticancer activities against human cell lines or in vivo, with minimal activity towards non-cancerous cells. Several studies have confirmed the anticancer potential of bacteriocins. However, more in vivo studies are necessary to fully elucidate and validate the clinical potency of bacteriocins as anticancer therapeutic agents.

Food applications

The application of bacteriocins in the food system has been extensively studied since their discovery. Bacteriocins are naturally synthesized and ready-to-use, without color, taste, odor, or impact on the sensory properties of food. They also demonstrate stability at high temperatures and low pH, making them increasingly important in the food sector (Perez et al. 2014; Abbasiliasi et al. 2017; Yang et al. 2018; Sanguyo et al. 2021; Shafique et al. 2022; Field et al. 2023; Yu et al. 2023). The suitability of bacteriocins for extensive application in the food system leverages several beneficial aspects of food production. Bacteriocins are able to (a) decrease the risk of transmission of foodborne or zoonotic pathogens and food poisoning, (b) improve the shelf life of food, (c) decrease economic losses due to disease outbreaks, food spoilage, and recalls, (d) preserve the nutritional value of food through the reduction of the intensity of physical treatments, (e) decrease processing costs and time, (f) provide a safe and sustainable alternative preservation approach for ready-to-eat and "novel” food, and (g) provide extra protection during temperature abuse episodes (Gálvez et al. 2007; Hu et al. 2014; Darbandi et al. 2022). While various aspects of bacteriocin applications within the food system, including food preservation, fermentation, and protective culture, have been extensively reviewed (Deegan et al. 2006; Zacharof and Lovitt 2012; Perez et al. 2014; Bali et al. 2016; Ahmad et al. 2017; Lopetuso et al. 2019), we provide additional updates on the emerging and relevant potential of bacteriocin use in the food system.

Potential in antimicrobial food packaging

Despite the application of advanced technologies in the food industry, excessive economic loss as a result of microbial contamination and spoilage continue to constitute a major challenge globally. The application of antimicrobial agents, including bacteriocins, in antimicrobial packaging is specifically suitable for mitigating the risk of microbial contamination. The use of bacteriocin-coated packaging films to inhibit and control food spoilage has attracted considerable attention the recent years. These bacteriocins can either be directly coated onto the packaging film surface or incorporated into the matrix of the packaging film (Woraprayote et al. 2016; Ahmad et al. 2017; Benabbou et al. 2020). However, it is important to understand both the physicochemical properties and the mechanism(s) of action of the selected bacteriocin(s) for such use (O’Connor et al. 2015). Active bacteriocin coating serves to protect food products by continuously interacting with the packaged food and modifying the internal environmental conditions within the required shelf life (Gumienna and Górna 2021). In most instances, bacteriocins improve food quality by maintaining microbiological safety, improving nutritional and sensory properties, and extending shelf life (Santos et al. 2018; Mousavi Khaneghah et al. 2018; Sanguyo et al. 2021; Shafique et al. 2022; Yu et al. 2023). Food packaging films or polymers incorporated with bacteriocins directly inhibit the growth of microorganisms on the food surface, where most of the microbial food spoilage or contamination occurs (Ahmad et al. 2017; Gumienna and Górna 2021; Rivera-Hernández et al. 2021). Interestingly, most bacteriocins retain their antimicrobial activity during food processing. Their viability is not impacted by changes in temperature, sterilization, pasteurization, or other processing techniques (Santos et al. 2018; Gumienna and Górna 2021). The growing consumer demand for safe, natural, and chemical-free food has enabled food industries to explore the use of bacteriocins in food packaging, among other applications. Active bacteriocin-coated materials are highly promising sustainable solutions to enhance food safety and shelf life while retarding food contamination and spoilage.

For example, a polyethylene-based packaging film infused with plantaricin BM-1 produced by L. plantarum BM-1 showed antilisterial activity against L. monocytogenes for at least 120 days at room temperature (Zhang et al. 2017). Woraprayote et al. (2018) also demonstrated the inhibitory activity of Weissella hellenica-produced bacteriocin 7293 impregnated onto a biocomposite film (PLA/SP) with pangasius fish fillets against various foodborne pathogens, including A. hydrophila, S. aureus, L. monocytogenes, P. aeruginosa, and S. typhimurium. The adsorption of nisin on a wide variety of packaging films with antimicrobial activities has been successfully reported on polypropylene, ethylene vinyl acetate, polyethylene, polyvinyl chloride, acrylics, polyamide, and polyester. Nisin-incorporated coatings for poultry products have also been documented (Appendini and Hotchkiss 2002; Scaffaro et al. 2011; Tumbarski et al. 2018). Polyamide and polyethylene pouches coated with nisin preparation (Nisaplin®) and lacticin 3147 significantly reduced L. lactis subsp. lactis, S. aureus, and L. innocua during the storage of vacuum-packed cheese (Scannell et al. 2000). Pediocin coated on plastic bags and cellulose casings completely inhibited L. monocytogenes in meats during 3 months of storage at refrigeration temperature (Ming et al. 1997). Benabbou et al. (2020) also reported the antimicrobial properties of biocompatible and biodegradable chitosan films incorporated with divergicin M35 for the biocontrol of Listeria spp. in foods, especially minimally processed products, and ready-to-eat food. The success observed in these studies highlights the potential of bacteriocins in antimicrobial packaging by effectively inhibiting or limiting the growth of spoilage and pathogenic microorganisms in packaged food.

Potential as antibiofilm and sanitizers

Microorganisms mostly exist as sessile communities, known as biofilms, enclosed in an extracellular matrix typically composed of extracellular DNA, lipids, polysaccharides, etc. (Flemming et al. 2016). Biofilm formation by microorganisms in the food system makes them resistant to antimicrobials and difficult to remove from food production facilities, surfaces, and environments (Mathur et al. 2018). Many biofilm-forming species in the food industry are known human pathogens that can cause metal corrosion, changes in organoleptic properties of food, and disease (Colagiorgi et al. 2017; Kirtonia et al. 2021). Biofilms are commonly found on surfaces such as tanks, pipelines, glass, polyethylene, polypropylene, rubber, packaging tools, and wood (Kirtonia et al. 2021). Recently, the use of bacteriocins as antibiofilm agents in the food industry has been widely reported (Mathur et al. 2018; Kirtonia et al. 2021; Jiang et al. 2022; Zhang et al. 2022a, b). In a study by Bolocan et al. (2017), several bacteriocins including, subtilomycin, nisin Z, and lichenicidin demonstrated high antibiofilm activity against L. monocytogenes biofilms. These bacteriocins also significantly decreased the viability of already formed biofilms. Another study showed that nisin at the concentration of 4000 IU/ml reduced biofilm formation by 87, 57, and 30% for Salmonella Enteriditis, L. monocytogenes, and S. aureus, respectively (Mahdavi et al. 2007). Bacteriocin sonorensin exhibited inhibitory activity against S. aureus biofilms (Chopra et al. 2015). From their study, the inhibitory property of sonorensin was attributed to increased membrane permeability in S. aureus. Biofilms formed by fourteen Staphylococcus strains were inhibited by hyicin 4244, a circular sactibiotic secreted by S. hyicus 4244 (Duarte et al. 2018). Hyicin 4244 decreased biofilm-forming ability, number of cells, cellular viability, and proliferation of sessile cells within already formed biofilm.

While the combination of nisin with enterocin B3A-B3B resulted in a 2-log decrease in L. monocytogenes biofilms on the surface of stainless steel within 24 h, nisin mixed with ethanol however resulted in a 5-log reduction of Salmonella and E. coli biofilms on stainless steel surfaces within 15 min (Phongphakdee and Nitisinprasert 2015; Al-Seraih et al. 2017). Industrial application of bacteriocins as antibiofilm agents or sanitizers may require a longer period to achieve significant bacterial reduction. However, bacteriocin combination with other antimicrobials can result in rapid bacterial reduction and biofilms clearance. Further studies are needed to explore the potential of bacteriocins as antibiofilm agents in the food industry, focusing on unraveling their mechanism of action and spectrum of activity.

Agriculture and veterinary medicine

Antibiotics have been routinely used in agriculture, either for treating or preventing animal diseases or as growth promoters. This practice has significantly contributed to the increased emergence and spread of antimicrobial-resistant pathogens from animals to humans (Ben Lagha et al. 2017). To address the issue of AMR in animal production, many countries have prohibited antibiotic use as growth promoters in animal production (European Commission 2005; AccessScience Editors 2017; Prescott 2019; Field et al. 2023; WOAH 2023). Therefore, the application of bacteriocins and/or bacteriocin-producing strains as growth promoters, prophylaxis, or therapeutics in agriculture has been considered viable and sustainable alternatives to antibiotics.

Potential as prophylactic and therapeutic agents

Dairy animals often suffer from mastitis, which is an inflammation of the mammary gland resulting in considerable economic losses due to reduced milk quantity and quality. Mastitis is predominantly caused by S. aureus, S. dysgalactiae, S. uberis, Mycoplasma spp., and E. coli (Cheng and Han 2020). Several bacteriocins, including lacticin 3147 and nisin, have been shown to inhibit the etiological agents of mastitis, especially S. agalactiae and S. aureus in dairy cattle (Cao et al. 2007; Pieterse et al. 2010b; Klostermann et al. 2010; Field et al. 2021; Bennett et al. 2021; 2022; Heinzinger et al. 2023; Raheel et al. 2023). The United States FDA has approved the general use of a nisin-based preparation, Wipe Out® Dairy Wipes (Immucell, Portland, ME, USA), for mastitis control in lactating dairy cows. Klostermann et al. (2010) demonstrated the efficacy of lacticin 3147 in eliminating mastitis-causing S. uberis, S. dysgalactiae, and S. aureus after a 10-min teat dip treatment. Other bacteriocins, such as aureocins A70, A53, epilancin K7, entomocin, Pep5, kurstacin 287, bacteriocin ST91KM, uberolysin, nisin U, kenyacin 404, and epidermin, have shown anti-mastitis effects against S. aureus and S. agalactiae (Barboza-Corona et al. 2009; Pieterse et al. 2010a; Salvucci et al. 2012).

Microcin J25 has been used for Salmonella control in poultry (Stavric and D’Aoust 1993; Ben Said et al. 2020; Baquero et al. 2024). Divercin AS7, a bacteriocin produced by Carnobacterium divergens AS7 has been effective in controlling S. enterica Typhimurium, Campylobacter spp., and C. perfringens in both poultry and swine (Gillor et al. 2004; Stern et al. 2005; Udompijitkul et al. 2012). Our recent studies have demonstrated the antagonistic and pathogen-reducing activity of plantaricin EF producing-L. plantarum, alone and in combination with other potential probiotic strains against enterobacteria in poultry (Reuben et al. 2022) as well as other zoonotic pathogens such as Salmonella Typhimurium, S. Enteritidis, E. coli O157: H7, E. faecalis, and L. monocytogenes (Reuben et al. 2020). In another study involving boilers challenged with Pasteurella multocida, we found that dietary supplementation with novel multistrain probiotics containing plantaricin EF-producing L. plantarum attenuated mortality, clinical manifestations, and inflammatory reactions associated with P. multocida-induced fowl cholera (Reuben et al. 2021). Furthermore, the abundance of gut enterobacteria and P. multocida was also significantly reduced in birds supplemented with the multistrain probiotics containing plantaricin EF-producing L. plantarum. Similarly, the therapeutic potential of bacteriocin and a strain of bacteriocin producing L. plantarum was investigated on broilers experimentally infected with E. coli (Ogunbanwo et al. 2004). Treatment with bacteriocin or the producing L. plantarum strain reduced E. coli-associated infections and improved the overall health and well-being of the birds.

Potential as growth promoters

The prohibition of antibiotic use as growth promoters in animal production has created a void that must be filled with equally potent, safe, and sustainable alternatives. Bacteriocins and their producing strains have emerged as widely accepted and suitable growth promoters in animal production. Several studies have demonstrated the growth promotion effects of bacteriocins and bacteriocin-producing strains in various animal species including poultry, cattle, and swine (Gillor et al. 2004; Cutler et al. 2007; McAllister et al. 2011; Józefiak et al. 2013; Reuben et al. 2021, 2022; Soltani et al. 2022a; Zhang et al. 2022a, b; Field et al. 2023).

The dietary supplementation with colicin E1 improved growth performance and significantly reduced F18-positive enterotoxigenic E. coli-associated postweaning diarrhea in piglets (Cutler et al. 2007). Supplementation with L. salivarius Bacteriocin Abp118 induced intestinal microbiota modulation, leading to increased growth performance and feed conversion efficiency in pigs (Riboulet-Bisson et al. 2012). Grilli et al. (2009) observed improved growth performance in C. perfringens infected broiler chickens supplemented with pediocin A alone or in combination with the producing strain. Similarly, the inclusion of nisin in the diet of broiler chickens beneficially modulated gut microbiota and significantly enhanced feed conversion and growth performance (Józefiak et al. 2013). Supplementation with plantaricin EF-producing L. plantarum, alone or in combination with other probiotic strains including E. faecium C14 and P. pentosaceus I13, improved haemato‐biochemical parameters, intestinal health, and growth in broilers (Reuben et al. 2022). Dietary supplementation of broiler feed with bacteriocin microcin J25 significantly improved performance, intestinal microbiota composition, and diversity, while reducing systemic inflammatory markers and levels of faecal E. coli and Salmonella (Wang et al. 2020b). These studies demonstrate the potential of bacteriocins or bacteriocinogenic strains as viable alternatives to antibiotics for growth promotion in animals.

Potential in sustainable aquaculture

The aquaculture supply chain is continuously exposed to multiple physical, chemical, and biological hazards, especially a wide range of pathogenic organisms. This impacts the quality and safety of aquaculture and its products. Minimizing microbiological hazards often involves the use of antibiotics, which enhances the selective pressure for the emergence and spread of superbugs and drug residues in both aquaculture products and their environment (Gillor et al. 2008; Wang et al. 2019a; Stentiford et al. 2022). However, in recent years, substantial attention has been given to the use of bacteriocins in aquaculture mostly for aquaculture processing and disease mitigation, improvement of water quality, and enhancement of sensory quality and shelf life (Wang et al. 2019a). Bacteriocin cloning and heterogeneous expressions from producing strains have demonstrated great potential in designing robust microbial cell factories capable of producing potent bacteriocins (Xu et al. 2019; Feito et al. 2023). Through this advancement, Feito et al. (2022) and Contente et al. (2023) engineered a recombinant multi-bacteriocinogenic strain (L. cremoris WA2-67) to produce three bacteriocins: garvicin A, Q, and nisin Z. The three recombinant bacteriocins, especially nisin Z, beneficially enhanced immune functions and growth performance while inhibiting pathogen colonization in rainbow trout (Oncorhynchus mykiss, Walbaum) (Contente et al. 2023). Bacteriocin-like substances (BLS) obtained by co-cultures of E. faecium MU8 with Aeromonas veronii showed significant antimicrobial activity against major pathogens of Nile tilapia, including Aeromonas jandaei and A. veronii (Promrug et al. 2023). Bacteriocin production through co-cultures of Gram-negative-inducing strains with Gram-positive bacteriocin-producing strains is now used to increase bacteriocin biosynthesis and yields (Liu et al. 2021; Promrug et al. 2023).

Bacteriocins such as enteromycin F4-9 and MC13, produced from E. faecalis F4-9 and E. faecium MC13 respectively, have shown broad inhibitory activity against both Gram-negative and Gram-positive bacterial pathogens of aquatic animals, including E. coli JM109, A. hydrophila, Vibrio harveyi, and V. parahaemolyticus (Pinto et al. 2009). Bacteriocin produced by A. media strain A199 has controlled V. tubiashii-infected Pacific oyster larvae (Gibson et al. 1998) and significantly reduced mortality due to saprolegniosis in eels (Lategan and Gibson 2003). The dietary inclusion of bacteriocin NPUST1 produced by Paenibacillus ehimensis NPUST1 reduced the counts of S. iniae and A. hydrophila and improved the growth performance of Oreochromis niloticus (Nile tilapia) (Chen et al. 2019). Plantaricin FGC-12 applied to Whiteleg shrimp (Penaeus vannamei) inhibited V. parahaemolyticus by causing cell wall perforation (Hu et al. 2013).

Furthermore, bacteriocin-like substances obtained from LAB associated with the gut of Mugil cephalus L (grey mullet) improved water quality, inhibited the growth of L. garvieae and reduced microbial-associated morbidity and mortality in aquatic animals (Lin et al. 2013). In addition to their pathogen inhibitory properties, bacteriocins also improve the sensory properties and shelf life of aquatic products (Cortesi et al. 2009; Alzamora et al. 2012).

Potential as plant growth promoters

So far, only bacteriocins of Bacillus spp. have been extensively studied and mostly used in plant production (Nazari and Smith 2020; Negash and Tsehai 2020). Bacteriocins bacthuricin F4 and thuricin 17 are produced by different B. thuringiensis strains, especially B. thuringiensis BF4 and NEB17. These bacteriocins, along with bacteriocin C85 secreted by B. cereus UW85, have been reported to possess growth promotion properties in plants (Negash and Tsehai 2020). Applying a cocktail containing the combination of the 3 bacteriocins and their producing strains increased photosynthesis by 6%, plant dry weight by 15%, root nodulation by 21%, and leaf area in corn, soybean, and tomato plants when compared with controls. These bacteriocins exhibit bacteriocidal and bacteriostatic activities that promote disease resistance in plants.

Mirzaee et al. (2021) recently reported that plant-produced bacteriocins inhibit different plant pathogens while conferring resistance to diseases in tomatoes. Furthermore, other bacteriocins such as amylocyclicin, Bac 14B, Bac-GM17, putidacin, and cerein 8A have been used for both antimicrobial activity and growth promotion in plants (Cherif et al. 2001, 2008; Hammami et al. 2009; Prudent et al. 2015).

Commercialization of bacteriocins: patent and market perspectives

While the current report of the World Intellectual Property Organization (WIPO) (https://www.wipo.int/portal/en/index.html) shows 1127 bacteriocins-related patent applications published, the Espacenet and Lens global patent search engines (https://www.epo.org/ and https://about.lens.org/) report 10,790 and 10,846 patents, respectively (Fig. 4). Over the past three decades, there has been a consistent increase in bacteriocin-related patent publications, filings, and approvals. The leading countries in patent applications are the USA, China, Canada, the Republic of Korea, Japan, and Australia. The top applicants include Colgate Palmolive Co, Unilever Plc, Unilever Nv, University of California, Coca-Cola Co, Chr Hansen As, and US Agriculture (Figures S2 and S3). The fascinating properties of bacteriocins contribute to their widespread acceptance and market potential.

Fig. 4
figure 4

Bacteriocin patent publication, filing, and approval

Full size image

In 1969, the Food and Agriculture Organization/World Health Organization (FAO/WHO) of the United Nations approved the general use of nisin as a food preservative. Subsequently, the European Union (Directive 83/463/EEC; Directive 95/2/EC), United States (FDA 21CFR), and Canada [Health Canada (NOP/ADP-0028)] granted similar approvals in 1983, 1988, and 2017, respectively. Although most commercially available bacteriocins especially nisin (Nisaplin™, Biosafe™, Oralpeace™), leucocin A (Bactoferm™ B-SF-43), sakacin (Bactoferm™ B-2, BactofermTM B-FM), and pediocin PA-1 (Microgard™, Alta 2341), are primarily used as food preservatives (Daba and Elkhateeb 2020; Cesa-Luna et al. 2021; Naskar and Kim 2021), others such as colicins and salmocins, intended for use as antibacterial agents, have received FDA approval (Hahn-Löbmann et al. 2019). In 2019, the FDA approved five bacteriocin preparations including, SalE1a, SalE1b, SalE2, SalE3, and SalE7 (Nomad Bioscience GmbH) for use as antimicrobial agents on meat, poultry, fish, and egg products (https://www.fda.gov/media/135524/download) The five bacteriocins were derived from non-typhoidal bacteriocinogenic Salmonella strains, and can be used individually or in combination. Duramycin (Moli1901) (AOP Orphan Pharmaceuticals AG), a commercially available bacteriocin, has been used in patients for the treatment of cystic fibrosis in humans (Grasemann et al. 2007; Steiner et al. 2008). Similarly, Delvo® Nis (DSM, Delft, Netherlands), Nisin Z® (Handary, Brussel, Belgium), and Nisaplin® (Danisco, Copenhagen, Denmark) have been approved for commercial use (Soltani et al. 2021a).

Bacteriocin-producing protective cultures, such as C. divergens M35, Leuconostoc carnosum 4010 (Danisco, HOLDBAC®) and C. maltaromaticum CB1 have been approved by several countries for use in the food industry (https://members.wto.org/crnattachments/2017/SPS/CAN/17_0131_00_e.pdf; https://www.canada.ca/en/health-canada/services/food-nutrition/public-involvement-partnerships/use-microbiological-preparation-carnobacterium-maltaromaticum-strain-certain-ready-meat-poultry-products/document.html). Nisin-based commercially available bacteriocins approved by the USDA, Teatseal® (Zoetis, USA), Wipe-Out® Dairy Wipes and Mast Out® (Immucell Corporation, USA) are commonly used as anti-mastitis agents in dairy cows (Soltani et al. 2021a). Additionally, nisin-incorporated soy-derived packaging films have been commercialized as an antimicrobial food package to inhibit Listeria (Ahmad et al. 2017). Several bacteriocin products, including sakacin (Bactoferm FLC®, Chr. Hansen, Hørsholm, Denmark), NVB302, Moli1901 (Actinoplanes liguriae NCIMB41362), mutacin 1140 (S. mutans JH1000), pediocin (Fargo 23, Quest International, B.V.), and NAI-107 (Microbispora corallina), are currently at various phases of clinical trials for subsequent use in health and agrifood systems (Soltani et al. 2021a; Cesa-Luna et al. 2021).

Challenges and limitations of bacteriocin application and future research

Despite increasing research on bacteriocin discovery, characterization, and application over the past decades, only a few have been commercially applied. While bacteriocins are generally believed to be safe, concerns about their cytotoxicity against eukaryotic cells, stability, immunogenicity, development of resistance, unpredictable biofunctions, and high production costs have raised doubts about their application. These concerns necessitate extensive safety evaluations of each bacteriocin before final approval and use in health and agrifood systems.

Several reports have demonstrated the safety and non-cytotoxicity of bacteriocins; however, others have shown varying (low) degrees of cytotoxicity in both in vitro and in vivo experiments (Pulse et al. 2019; Baños et al. 2019; Cebrián et al. 2019, 2023; Wang et al. 2022; Abdille et al. 2022; Heinzinger et al. 2023). The minimal cytotoxicity observed in most studies was due to significantly higher concentrations of bacteriocins and prolonged experimental exposure, beyond the required minimum inhibitory concentrations (MIC) for pathogen inhibition or food protection. At significantly higher concentrations (above the MIC), bacteriocin PA166 showed minimal cytotoxicity on Vero and NR8383 cells, as well as in the mouse infection model (Wang et al. 2022). Similarly, enterocin AS-48, bacteriocin OG716, and dermaseptin only exhibited mild cytotoxicity with prolonged treatment or at significantly higher concentrations in Golden Syrian hamsters, B2 BALB/c mice, and Albino Wistar rats (Pulse et al. 2019; Baños et al. 2019; Abdille et al. 2022). Additionally, cytolysin, a bacteriocin produced by E. faecalis, showed broad cytotoxicity to various cell lines, including intestinal epithelial cells, leucocytes, erythrocytes, and human retinal cells (Coburn and Gilmore 2003; Cox et al. 2005). It is important to note that the cytotoxicity of bacteriocins can be influenced by factors such as purity, concentration, the specific mammalian cell line or experimental model used, and host-associated factors (e.g., in vivo experiments) (Cavicchioli et al. 2018; Soltani et al. 2021a; Cebrián et al. 2023). Certain eukaryotic cell lines may be more sensitive to particular bacteriocins than others, with differences attributed to cell type, composition of cell membranes, permeability, and hydrophobicity (Das and Goyal 2014; Soltani et al. 2021a; Abdille et al. 2022).

Physiological and physicochemical parameters can influence the stability and bioactivity of bacteriocins in the host or food matrix. Several reports have shown rapid inactivation or enzymatic degradation of bacteriocins produced in situ, orally ingested, or applied to food matrices (De Vuyst and Leroy 2007; Fernandez et al. 2013; Md Sidek et al. 2018; Holcapkova et al. 2018; Flynn et al. 2019, 2022; Soltani et al. 2021b). Despite their potential for applications in clinical and agrifood systems, class II bacteriocins are highly sensitive to proteolytic enzymes, which reduces their bioactivity when used (Soltani et al. 2021a). For instance, pediocin PA-1, nisin A, and microcin J25 were inactivated or degraded when exposed to intestinal contents and proteolytic enzymes (Kheadr et al. 2010; Gough et al. 2017; Naimi et al. 2018). However, through encapsulation and bioengineering, microcin J25 or nisin showed some stability in the presence of proteolytic enzymes and under intestinal conditions (Field et al. 2015, 2019). Engineering bacteriocins can help create resistant bacteriocin derivatives that can withstand harsh gut conditions and enzymatic degradation while maintaining their bioactivity. Additionally, systems like encapsulation and coating have been developed to protect and precisely deliver bacteriocins to the intended site of action or within specific food matrices, allowing them to exert their biological functions (Gomaa et al. 2017; Gough et al. 2018; Holcapkova et al. 2018; Flynn et al. 2019, 2022).

To avoid any sudden or unexpected immune responses, the immunogenicity of bacteriocins should be carefully examined, especially when intended for use in humans and animals. Generally, several bacteriocins, including pyocins S2, S5, AP41, and L1, bacteriocins LR14, TSU4, JCM1132, and P34, plantaricin E/F, mutacin 1140, microbisporicin, actagardine, and duramycin have been reported to be non-immunogenic in in vivo studies (McCaughey et al. 2016; Ongey et al. 2017; Sahoo et al. 2017; Hanny et al. 2019; Wang et al. 2019c). However, prolonged administration of some bacteriocins, such as pyocin S5 and Nisaplin®, has been shown to elicit mild immunogenicity (de Pablo et al. 1999; Scholl and Martin 2008; McCaughey et al. 2016). Furthermore, some bacteriocins have also displayed unique and unpredictable properties, expressing both bacteriocin and virulence factors. Listeriolysin S (LLS) and pneumocins exhibit both virulence and bacteriocin properties and are highly expressed in the gut of orally infected mice (Quereda et al. 2016; Wholey et al. 2019). Both LLS and pneumocins are antibiotic-induced and can alter the host intestinal microbiome, enhancing intestinal colonization with L. monocytogenes and S. pneumoniae (Kjos et al. 2016; Quereda et al. 2016; Wholey et al. 2019). Bacteriocins may exert different sudden and unpredictable effects when used in humans and animals. Therefore, their immunogenicity and other emerging co-bioactive properties such as virulence factors should be elucidated before use.

Another major challenge of bacteriocin application in health and agrifood systems is their low yields and high cost of large-scale industrial production, purification, and prolonged storage. For commercial and economic purposes, bacteriocins need to be produced in large and sufficient quantities. For research purposes, crude, unpurified, and concentrated bacteriocins are often produced using costly and complex media that are mostly not food or pharmaceutical-grade (Garsa et al. 2014; Abbasiliasi et al. 2017; Johnson et al. 2018). The bottleneck for efficient and commercial production of bacteriocins is the need for complex media that optimally support the metabolism and auxotrophies of the producing strains (Ongey and Neubauer 2016; Goldbeck et al. 2021). Additionally, industrial-level purification and biopreservation of bacteriocins is another limitation for commercial-scale bacteriocin production. In most cases, laboratory-based purification protocols are usually not suitable at the industrial scale mostly due to the high cost of the purification processes (Garsa et al. 2014; Mesa-Pereira et al. 2018; Juturu and Wu 2018). Nevertheless, chemical synthesis has been recently proposed as a viable alternative for the industrial-scale production of bacteriocins (Bédard and Biron 2018; Bédard et al. 2018; Desiderato et al. 2023; Sevim and Güneş Altuntaş 2024). Industrial and large-scale production of active bacteriocins using chemical synthesis would further enhance the use of bioengineering and consequently, improve stability, spectra of antimicrobial activity, and pharmacological properties of bacteriocins in humans and agrifood systems (Bédard et al. 2018; Kuniyoshi et al. 2022; García-Vela et al. 2024). Efficient and cost-effective production and purification processes are essential for wider applications in health and agrifood systems. Additional research is necessary to further develop economical and low-cost production and purification processes of highly promising bacteriocins.

Finally, like other conventional antimicrobials, persistent exposure to bacteriocins can lead to the development of resistance in target bacteria. Bacteriocin resistance has been demonstrated for divercin V41, mesenterocin, leucocin A, pediocin and pediocin-like bacteriocins, lacticin 3147, lysostaphin, nisin, pyocin S2, mesenterocin, mundticin KS, etc. (Sakayori et al. 2003; Opsata et al. 2010; Collins et al. 2012; Inglis et al. 2016; López-González et al. 2018; Bhattacharya et al. 2019; Gradisteanu Pircalabioru et al. 2021). So far, bacteriocin resistance has been mostly studied in in vitro and model systems and can either be acquired (emerged from previously susceptible strains) or innate (naturally inherent in taxonomically related strains) (Bastos et al. 2015; Soltani et al. 2021a). Bacteriocin resistance mechanisms can include impermeability due to changes in cellular surfaces, enzymatic inactivation, changes in the antimicrobial peptide targets, entrapment by secreted molecules that can bind and neutralize bacteriocins, chemical modifications in membrane lipid composition, D-alanylation of teichoic acid, cellular filamentation, efflux pumps, and capsule synthesis to avoid contact with bacteriocins (Sakayori et al. 2003; Chifiriuc et al. 2014; Bastos et al. 2015; Kumariya et al. 2015, 2019; Soltani et al. 2021a). Rasch and Knøchel (1998) and Collins et al. (2010) separately reported up to 5.2 and 8.0% resistance of multi-sourced L. monocytogenes to pediocin PA-1 and pediocin-like bacteriocins respectively. The instances and mechanisms of bacteriocin resistance have been extensively reviewed (Bastos et al. 2015; Gradisteanu Pircalabioru et al. 2021; Soltani et al. 2021a). Some target microbial strains have developed multiple mechanisms of resistance which can be synchronously displayed against specific bacteriocins (Vadyvaloo et al. 2002; Lohans and Vederas 2012; Bastos et al. 2015; Kumariya et al. 2015). This can therefore lead to the emergence of bacteriocin-resistant phenotypes, which may constitute an additional burden to the rising antimicrobial resistance menace. Understanding these resistance mechanisms and developing countermeasures can significantly enhance the clinical application of bacteriocins. Additional research is needed to address these challenges and further develop safe, economical, and low-cost production and purification processes for bacteriocins.

Conclusion and prospects

The exacerbating global crisis of the emergence and spread of pathogens, antimicrobial resistance, dearth of novel antimicrobials, and the implementation of strict antibiotic-limiting policies in many countries necessitate a comprehensive approach to identify and apply widely accepted, potent, and safe alternative antimicrobials. Bacteriocins have invaluable and heterogeneous properties that make them suitable for use in human, animal, and food systems for disease prevention and treatment, microbiome modulation, growth promotion, and enhancing food quality, safety, and organoleptic properties, among other benefits.

Through bibliometric analyses, we have identified several prevailing trends in bacteriocin research. Firstly, there has been a significant increase in annual research outputs, which we believe reflects the growing global interest in bacteriocins. Secondly, we have observed a multidisciplinary participation in bacteriocin research, with contributions from various fields. Additionally, we have found that funding for bacteriocin research is relatively evenly distributed worldwide. The countries leading in bacteriocin-related research outputs are spread across the Northern and Southern Hemispheres. The majority of these research outputs are published by reputable publishes such as Elsevier, Springer Nature, Wiley, and the American Society of Microbiology. Interestingly, while bacteriocins research is primarily focused on microbiology, biotechnology, and food science, we have also discovered a significant number of outputs in emerging areas such as plant science, virology, polymer science, and biophysics. This suggests that bacteriocins may have applications in previously unknown fields, and we anticipate further research and applications in these areas in the coming years.

Harnessing the ubiquitous nature of bacteriocins could help in their exploitation for broad applications in innovative areas of the human, animal, and food systems. The food system is benefiting immensely from commercially available bacteriocins. However, the scope of bacteriocin applications in the food system could be expanded in areas such as [fermented] food microbiota modulation, antimicrobial packaging/coating, biosanitizers, antibiofilm, pre/post-harvest biocontrol, and functional food.

Furthermore, the use of bacteriocins in the modulation of human and animal microbiota can beneficially improve the composition, diversity, and richness of the microbiota, fostering health and well-being. Bacteriocin modulatory activity can provide a viable microbiome-based solution for the treatment and management of microbiome-associated diseases. Bacteriocins also have the potential for non-invasive bio-diagnosis and could be used for diagnosing both infectious and non-infectious diseases, thus complementing conventional diagnostic tools. In terms of agriculture, the growth-promoting effect of bacteriocins in both plants and animals would undoubtedly improve food security, safety, and quality, as well as promote sustainable agriculture and mitigate concerns associated with antibiotic use.

Through vigorous research, it is necessary to increase the potency and applications of bacteriocins in humans, using innovative approaches such as bioengineering, computational methods, artificial intelligence, nanotechnology, machine learning, microscopy techniques, chemistry, metabolic activity-based assays, and pharmacodynamics. These approaches will facilitate optimal and industrial-scale production of safe bacteriocins for general use.