Antibiotics have revolutionised the treatment of infectious disease and improved the lives of billions of people worldwide over many decades. With the rise in antimicrobial resistance (AMR) and corresponding lack of antibiotic development, we find ourselves in dire need of alternative treatments. Bacteriocins are a class of bacterially produced, ribosomally synthesised, antimicrobial peptides that may be narrow or broad in their spectra of activity. Animal models have demonstrated the safety and efficacy of bacteriocins in treating a broad range of infections; however, one of the principal drawbacks has been their relatively narrow spectra when compared with small-molecule antibiotics. In an era where we are beginning to appreciate the role of the microbiota in human and animal health, the fact that bacteriocins cause much less collateral damage to the host microbiome makes them a highly desirable therapeutic. This review makes a case for the implementation of bacteriocins as therapeutic antimicrobials, either alone or in combination with existing antibiotics to alleviate the AMR crisis and to lessen the impact of antibiotics on the host microbiome.

## Introduction

Antimicrobial resistance (AMR) has been recognised as one of the major threats to public health in the 21st century. In a report commissioned by the UK government in 2014, it was estimated that AMR could be responsible for 10 million deaths worldwide by 2050, with a global financial cost of $100 trillion [1]. Meanwhile, the Centers for Disease Control and Prevention (CDC) estimates the annual cost of AMR in the USA to be about$20 billion in direct healthcare costs and \$35 billion in additional costs to society due to lost productivity [2]. Apart from the human and financial costs associated with AMR, there are also ethical considerations that need to be addressed surrounding how we, as a society, respond and deal with the AMR crisis [3]. There are multiple reasons for the present AMR crisis, but significant factors include the incorrect/indiscriminate administration and use of antibiotics and a dry antibiotic development pipeline [4,5]. The CDC also recently estimated that, in the USA, ∼50% of antibiotics are incorrectly prescribed. Moreover, the use of antibiotics in agriculture has continued, despite undeniable evidence that this practice adds to the AMR crisis. Resistance to a key ‘last-resort’ antibiotic, colistin, has been observed in the USA, Europe and Asia [68]. We have also seen the rapid spread of resistance to another ‘last resort’ class of antibiotics, the carbapenems [9]. With the emergence of these new resistant strains and the emergence of pan-resistant bacteria, it is safe to say we have truly arrived in the much-predicted post-antibiotic era [10].

It is important that we acknowledge that broad-spectrum antibiotic therapy has revolutionised the treatment of infectious diseases within the last century, but we must also admit to unintended consequences of antibiotic use, such as potentially negative effects on the host microbiome and their potential toxicity [5,11]. Although the field of microbiome research is in its infancy relative to that of antibiotic therapy, evidence strongly suggests that the composition of the microbiome can be an indicator of health and is likely to be involved in many aspects of human health and disease [12]. Strides in DNA sequencing technology and bioinformatics have increased our understanding of the role of the microbiome in a variety of disease states. Indeed, the administration of antibiotics in early life and the subsequent disruption of the microbiota may contribute to the risk of obesity in later life [13,14]. Furthermore, when subjected to broad-spectrum antibiotic therapy, non-target commensal microbes may evolve and/or acquire resistance mechanisms to evade the effects of the antibiotic, thereby contributing to the antibiotic resistance crisis.

Bacteriocins represent a class of powerful antimicrobial peptides that may provide at least part of a solution to the AMR crisis. We aim to demonstrate their efficacy in the treatment of infectious disease and their reduced impact on the host microbiome by comparison with broad-spectrum antibiotic therapy.

## Bacteriocins: potent antimicrobial peptides

Many excellent reviews have been written about bacteriocins [11,15,16], but in brief they are a diverse group of peptides that may be classified into three distinct groups: class I (modified), class II (unmodified or cyclic) and class III (>10 kDa peptides). Apart from their potent antimicrobial activity (with minimum inhibitory concentrations [MICs] often in the nanomolar range), they have also been shown to have antiviral [17], anticancer [18] and immunomodulatory properties [19]. Bacteriocins typically have a narrow spectrum of activity, but broad-spectrum peptides are also present in this class of antimicrobials (e.g. nisin and lacticin 3147 inhibit a wide range of Gram-positive bacteria). As a result, these peptides may be suitable for treating infections of unknown aetiology, using broad-spectrum bacteriocins, or may allow more precise targeting of known infectious agents using highly active narrow-spectrum bacteriocins. Bacteriocins are gene-encoded, which makes them amenable to genetic alterations to improve functional characteristics. Furthermore, their toxicity is low and they may be administered as either purified peptide or produced in situ by bacteriocin-producing probiotic bacteria [11]. Bacteriocins are also known to interact with a variety of receptors, which are different from those targeted by antibiotics, making cross-resistance less likely [20]. Although a more targeted approach may still ultimately lead to resistance development in the infectious agent, it does reduce the likelihood of resistance development in commensal populations outside of the target range of the bacteriocin. Resistance mechanisms involving the class II receptors, the mannose phosphotransferase system, have been identified [21] along with a variety of resistance mechanisms to the class I lantibiotics [22].

## The microbiota perspective

The term ‘superorganism’ or ‘holobiont’ has commonly been applied to describe the relationship that exists between humans and their commensal microbes and viruses [23]. Understanding the role of the microbiota in health and protecting its diversity during the treatment of infectious disease is a key element of why bacteriocins may be suitable as alternatives to antibiotics.

The two-peptide sactibiotic bacteriocin Thuricin CD is a narrow-spectrum bacteriocin. Thuricin CD is highly active against one of the main causative agents of antibiotic-associated diarrhoea (AAD), Clostridium difficile, which is responsible for 20–30% of AAD cases [24]. Briefly, AAD is caused by a disruption of the microbiota (often referred to as dysbiosis) following broad-spectrum antibiotic treatment and notably has a recurrence rate of 15–60% [25]. Thuricin CD was shown to exhibit comparable activity to both vancomycin and metronidazole [two antibiotics used for the treatment of AAD which has progressed to C. difficile-associated disease (CDAD)]. Importantly, it showed almost no effect on microbial diversity when compared with both metronidazole and vancomycin in a distal colon model [26]. The modified R-Type bacteriocin Av-CD291.2 has also been shown to prophylactically inhibit colonisation of C. difficile in a mouse model without perturbing the microbiota [27]. There are other broad-spectrum bacteriocins which are attractive therapeutic agents by virtue of their activity against C. difficile, but while the broad-spectrum lantibiotic lacticin 3147 is effective at killing C. difficile, it has a significant impact on the resident microbiome populations such as Bifidobacterium, Lactobacillus and Enterococcus species [28]. It has also been shown that a commercially available product containing the lantibiotic nisin, Nisaplin®, can eliminate a C. difficile infection when added at a concentration of 20× MIC in a simulated human colon model. However, a significant decrease in the total microbiota count was observed, with Gram-positives being adversely affected [29].

Notably, in recent years, the emergence of vancomycin-resistant Enterococci (VRE) has become a great concern and therefore raises the issues surrounding the efficacy of treating CDAD with vancomycin if it presents a risk to the general population and the spread of antibiotic resistance. In this light, the treatment of CDAD with bacteriocins could be a valuable alternative to vancomycin. When VRE development has taken place, it has been shown that mice colonised with VRE can be decolonised through the use of an Enterococcus probiotic containing a conjugation defective plasmid which produces a bacteriocin named Bac-21 [30].

A defensin-like bacteriocin, bactofencin A, displays in vitro activity against Listeria monocytogenes and Staphylococcus aureus [31,32]. Although one might expect this medium to broad-spectrum antimicrobial peptide to cause drastic changes in the host microbiome, this was in fact not the case. It was observed that the bactofencin peptide only subtly modulated an ex vivo host microbiome (distal colon model) when introduced as a bacteriocin-producing probiotic or purified peptide [33]. While the purified peptide resulted in higher levels of beneficial microbes such as Bifidobacterium, it was also associated with lower levels of Clostridium, which has been linked to obesity and gut pathogenesis [34]. Interestingly, although bactofencin does not show inhibitory activity in vitro against strains from the genera Clostridium, Fusobacterium and Bacteroides, the reduction in these populations in the bactofencin-treated faecal samples indicates that the consequence of bactofencin altering the overall microbiota structure affects, directly or indirectly, these normally insensitive populations when in the gut environment [33].

It has also been shown, using bacteriocin-producing probiotic strains and their isogenic mutants, that the production of bacteriocins can aid the colonisation of a murine host [35]. Sequencing data revealed that although bacteriocin production by the probiotics did not affect bacterial diversity at the phylum level, broad-spectrum bacteriocins (enterocins and garvicin ML) had a more significant impact on the genus/family diversity of the host microbiome than narrow-spectrum bacteriocins (sakacin A, plantaricins and pediocin PA-1).

## Bacteriocins in animal models

Bacteriocins have been shown to be effective in the treatment of a variety of bacterial infections using two delivery methods, either as purified peptides (Table 1) or when delivered in situ by probiotics [43].

Table 1
Bacterial infections in animal models successfully treated using purified bacteriocins
Peptide Strain inhibited Model Purity Reference
Nisin F S. aureus Immunosuppressed Wistar rats Semi-pure [36
S. aureus Brushite cement in BALB/c mice Semi-pure [37
Lacticin NK34 S. aureus/S. simulans ICR mice Semi-pure [38
Nisin V L. monocytogenes BALB/c mice Pure [39
Divercin V41 L. monocytogenes BALB/c mice Pure [40
Mutacin B-Ny266 S. aureus Unknown Pure [41
Mersacidin Methicillin-resistant Staphylococcus aureus (MRSA) BALB/cA mice Pure [42
Peptide Strain inhibited Model Purity Reference
Nisin F S. aureus Immunosuppressed Wistar rats Semi-pure [36
S. aureus Brushite cement in BALB/c mice Semi-pure [37
Lacticin NK34 S. aureus/S. simulans ICR mice Semi-pure [38
Nisin V L. monocytogenes BALB/c mice Pure [39
Divercin V41 L. monocytogenes BALB/c mice Pure [40
Mutacin B-Ny266 S. aureus Unknown Pure [41
Mersacidin Methicillin-resistant Staphylococcus aureus (MRSA) BALB/cA mice Pure [42

It has been hypothesised that there are three mechanisms by which bacteriocins mediate their producers’ probiotic properties [44]: (i) competitive inhibition: bacteriocins may support colonisation of the host through competitive inhibition of the autologous microbiota; (ii) pathogen inhibition: bacteriocins may interact directly with a pathogenic target; or (iii) immunomodulation: bacteriocins may act as signalling peptides, recruiting other bacteria or recruiting immune cells to the site of infection to aid elimination of the pathogen (Figure 1).

### Bacteriocinogenic probiotics can be utilised either prophylactically or therapeutically to treat an infection.

Figure 1.
Bacteriocinogenic probiotics can be utilised either prophylactically or therapeutically to treat an infection.

M, M cell; Mac, macrophage; Mu, mucous; T, T cell; IEC, intestinal epithelial cell; DC, dendritic cell.

Figure 1.
Bacteriocinogenic probiotics can be utilised either prophylactically or therapeutically to treat an infection.

M, M cell; Mac, macrophage; Mu, mucous; T, T cell; IEC, intestinal epithelial cell; DC, dendritic cell.

### Preventing infection

Oral disease is a widely recognised as a major public health issue worldwide, with dental caries in industrial countries affecting 60–90% of school children and adults, making it the most prevalent human disease [45,46]. The concept of oral replacement therapy is an interesting example of prophylactic probiotic therapy, which may be used to treat dental caries and oral disease. The mutacin 1140 producing Streptococcus mutans BCS3-L1 may be suitable for replacement therapy as it has reduced cariogenic potential because it does not produce lactic acid, mediated through the removal of its entire lactic acid dehydrogenase operon [47]. Another interesting probiotic that has shown promise in the limitation of dental caries, plaque accumulation and acidification is Streptococcus salivarius M18. This strain has three plasmid and one chromosomally encoded bacteriocins, which is perhaps why it can colonise the oral cavity so effectively. It also produces two enzymes, urease and dextranase, which reduce the acidity of saliva and counteract plaque formation [48]. In a clinical trial, both the safety and efficacy of this strain's probiotic potential were demonstrated, and it was shown to significantly reduce plaque formation in subjects who received the probiotic, over those who received the placebo [49]. Furthermore, the treatment of children who have a high risk of dental caries development, with an oral formulation of the S. salivarius M18 probiotic (Carioblis®), was shown to reduce the likelihood of new dental caries development [50].

It has been demonstrated that dosing mice orally with the bacteriocin producer Lactobacillus salivarius UCC118 3 days prior to infection with L. monocytogenes resulted in a significant reduction in subsequent infection by L. monocytogenes [51]. Nisin Z and pediocin AcH have also been shown to reduce and prevent the colonisation of a mouse model with VRE, where the bacteriocinogenic probiotic was administered 8 days prior to infection [52]. It has also been demonstrated using a porcine model that Salmonella enterica serovar typhimurium shedding is reduced and disease symptoms of infection are alleviated when a mixture of five probiotic strains was administered 6 days before infection [53]. One of the probiotics, L. salivarius, produces salivaricin P, which can kill the other four strains in the probiotic mixture. Interestingly, this bacteriocinogenic strain dominated in the ileum (the primary attachment site of the infecting Salmonella), whereas it was only detected as a minor component in the faeces of the same animals. This suggests that bacteriocin production may play a role where colonisation can occur along the gastrointestinal tract [54]. The concept of using prophylactic probiotics to competitively colonise a pathogen's niche could be an effective strategy in agriculture to reduce antibiotic usage. If, as expected, regulations limiting the use of antibiotics in agriculture come into force, probiotics may be an invaluable alternative.

Acute otitis media (AOM) is a type of inflammatory disease of the middle ear, characterised typically by rapid inflammation, potential tympanic membrane perforation, along with fullness and erythema. It has been reported that the levels of normal α-haemolytic Streptococcus colonising the nasopharynx of otitis-prone children are much lower than those in healthy individuals and that recolonisation can significantly reduce the episodes of AOM [55,56]. It has been demonstrated that treating otitis-prone children with a history of AOM with a nasal spray containing safe Streptococcus salivarius 24SMB (a strain which produces a bacteriocin-like substance) reduces the incidence rates of AOM compared with those of the placebo-treated group [57].

### Treating infection

Helicobacter pylori infection and colonisation results in a variety of disease states and may even lead to the development of gastric carcinoma. More recently, the prevalence of antibiotic-resistant H. pylori has been increasing, creating a need for a new therapeutic agent [58]. It has been shown in mice that eradication of H. pylori was achieved using a bacteriocinogenic probiotic treatment of Pediococcus acidilactici BA28 [59]. Using a mixture of cranberry juice and the bacteriocin-producing probiotic culture Lactobacillus johnsonii str. La1 supernatant, the carriage of H. pylori was also reduced in children after 3 weeks of treatment [60].

One limitation to the use of bacteriocinogenic probiotics as therapeutics is their ability to survive gastrointestinal conditions and deliver bacteriocins to the site of infection. It has been shown that P. acidilactici UL5 and Lactococcus lactis ATCC 11454 can produce the bacteriocins pediocin PA-1 and nisin, respectively, in situ under simulated upper gastric conditions [61]. Interestingly, the in vitro activity of a bacteriocin does not always correspond to the in vivo activity, where the bacteriocin is sometimes more or less active in an animal model, as is the case with mersacidin, which is more active in vivo than in vitro [62].

## Bacteriocins against Gram-negatives

Comparatively speaking, Gram-negative bacteria are relatively insensitive to bacteriocins compared with their Gram-positive counterparts, largely owing to their outer membrane, which acts as a physical barrier. Until recently, the treatment of Gram-negative infections with bacteriocins has not been favoured due to the efficacy of conventional antibiotics in the treatment of these infections. The rise of antibiotic-resistant Gram-negative bacteria to the last line of antibiotics [6] means that the treatment of these infections using bacteriocins can no longer be ignored.

Widespread use requires a solution to the relative insensitivity of Gram-negative microorganisms. One possibility is to use bacteriocins in combination with other antimicrobial agents, including conventional antibiotics. Although conventional antibiotics will have an impact on the host microbiota (as previously discussed), certain bacteriocin/antibiotic combinations can be synergistic [6366] and therefore lead to a reduced dose of both antimicrobial agents needed to treat an infection, thereby lowering the potential effect on the host microbiome and the cytotoxic effects on the host, and may potentially reduce the development of resistance.

Success of antibiotics is also hindered by Gram-negative bacteria residing within biofilms, where they are highly resistant to antibiotic treatments. Bacteriocin/antibiotic combinations have shown great promise in overcoming biofilm-mediated resistance for important Gram-negative pathogens such as Pseudomonas aeruginosa [67] and Escherichia coli [68].

Although this review mainly focuses on Gram-positive bacteriocins, it is important also to identify Gram-negative bacteriocins, which may have potential therapeutic significance. Microcins are ribosomally synthesized peptides commonly produced by Gram-negative bacteria, which are active against Gram-negative strains, and are an interesting alternative to Gram-positive bacteriocins. They have been shown to display potent antimicrobial activity in vitro [69,70] and more recently also in vivo [71]. It has been demonstrated that the microcin producer E. coli Nissle 1917 (EcN) can prevent colonisation of competing Enterobacteriaceae in the gut, while still having a minimal impact on the diversity of the gut microbiota. However, EcN microcins exhibit their mechanism of action by targeting specific siderophore receptors on other Enterobacteriaceae, which are only displayed during iron starvation, making their spectrum of activity quite narrow. Additionally to its prophylactic applications, EcN has also been demonstrated to reduce inflammation and weight loss associated with Salmonella infections. Another microcin produced by E. coli G3/10, microcin S, has been shown to inhibit other E. coli strains and, furthermore, can prevent the adherence of Enteropathogenic E. coli to intestinal epithelial cells [72].

## Overcoming the limitations/outlook

In previous decades, significant emphasis was placed on functional characteristics of bacteriocins, such as spectrum of activity, pH and temperature stability, which were essential for the use of bacteriocins in food applications. For their use as therapeutics, additional characteristics such as proteolytic resistance, stability and solubility of bacteriocins will also be important.

With advancements in the field of bioengineering, many intrinsic limitations have been overcome, and it has been shown using the prototypic lantibiotic nisin that bioengineering strategies can improve functional qualities such as antimicrobial activity [7376], solubility [77,78] diffusion properties [79] and effectiveness against Gram-negative bacteria [75]. Indeed, similar bioengineering strategies could be applied to other bacteriocins once suitable expression systems have been developed. Although the sensitivity of bacteriocins to proteolytic cleavage was previously regarded as a desirable trait when using these peptides as food preservatives, it does represent a major concern with regard to their administration and widespread use, both orally and intravenously. Bioengineering strategies could be once again used to manipulate peptide residues, so they are no longer recognisable by host proteases and therefore are not proteolytically cleaved, thereby improving peptide functional qualities [80]. Notably, the therapeutic application of the prototypic bacteriocin nisin has been in part hampered by its sensitivity to host proteases [81]. Other approaches include prospecting for bacteriocins that display innate resistance to proteases, as was achieved with pseudomycoicidin [82], which is naturally resistant to trypsin due to the presence of a thioether ring structure. The field of bioinformatics and the use of such programmes as BAGEL 3.0 [83] and antiSMASH [84] could be a fundamental aspect of this prospecting, as these bacteriocin amino acid prediction tools from genome sequences may also allow researchers to identify protease-resistant peptides before investing large amounts of time and effort in characterising such bacteriocins. Finally, understanding bacteriocin pharmacodynamics and pharmacokinetics is also essential to their safe implementation as therapeutics, which has been under-investigated in comparison with other aspects of bacteriocin research. If bacteriocins are indeed to become an alternative to conventional antibiotics, a greater emphasis must be placed on research surrounding these host–drug interactions, such as was achieved with MU1140 [85]. Addressing these limitations of bacteriocin research to date could provide a turning point for the flagging interest of the pharmaceutical industry and make bacteriocins an attractive therapeutic alternative to current antibiotics [10].

Although there is considerable evidence that narrow-spectrum bacteriocins have a minimal effect on the host microbiome by comparison with current broad-spectrum antibiotics, it should also be recognised that more work in this regard is needed to strengthen the argument for the use of bacteriocins as antibiotics, along with overcoming the previously outlined limitations. Ultimately, we believe, given the safe history of use of bacteriocins in food and the large body of literature surrounding this field, that they are useful candidates for antimicrobial therapeutics as the AMR crisis continues to worsen.

Summary
• Antimicrobial resistance (AMR) is a major threat to public health requiring immediate attention.

• Bacteriocins are potent antimicrobial peptides, active in the nanomolar range and have a reduced impact on the host microbiota.

• Bacteriocins may be used to treat a broad range of infections and can be delivered as purified peptides or as bacteriocinogenic probiotics.

• Combining antibiotics and bacteriocins is a strategy to reduce the negative impacts on the host microbiota and also alleviate the AMR crisis.

• Overcoming the current limitations of bacteriocin-based therapeutics should be a key goal of bacteriocin research in the future.

## Abbreviations

antibiotic-associated diarrhoea

•
• AMR

antimicrobial resistance

•
• AOM

acute otitis media

•

Clostridium difficile-associated disorder

•
• CDC

Centres for Disease Control and Prevention

•
• EcN

Escherichia coli Nissle

•
• MIC

minimum inhibitory concentration

•
• VRE

vancomycin-resistant Enterococci.

## Author Contribution

K.E. drafted the manuscript. R.P.R. and C.H. revised and approved the final manuscript.

## Funding

K.E., C.H. and R.P.R. are supported by the Irish Government under the National Development Plan, through the Food Institutional Research Measure, administered by the Department of Agriculture, Fisheries and Food, Ireland [DAFM 13/F/462]. C.H. and R.P.R. are also supported by the SFI Investigator awards [10/IN.1/B3027] and the APC Microbiome Institute under grant number SFI/12/RC/2273.

## Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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