Human microbiota peptides: important roles in human health

Contents

• 1 Introduction

• 2 Methodology

• 3 Human microbiota and microbiome are hosts of important peptides

• 4 In-depth investigation of human microbiota-generated peptides and their significance in human disorders
  • 4.1 Critical role of peptides generated from Firmicutes (Bacillota) in human disorders
  • 4.2 In-depth analysis of Proteobacteria-derived peptides
  • 4.3 Biological roles of Actinobacteria (Actinomycetota)-derived peptides
  • 4.4 In-depth analysis of Bacteroidetes-derived peptides
  • 4.5 Biological functions of Fusobacteria-derived peptides with their role in human disorders

• 5 Future challenges and conclusive remarks

• 6 Data availability

• 7 Conflicts of interest

• Acknowledgements

• References

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Abstract

Covering: 1974 to 2024

Human microbiota consist of a diverse array of microorganisms, such as bacteria, Eukarya, archaea, and viruses, which populate various parts of the human body and live in a cooperatively beneficial relationship with the host. They play a crucial role in supporting the functional balance of the microbiome. The coevolutionary progression has led to the development of specialized metabolites that have the potential to substitute traditional antibiotics in combating global health challenges. Although there has been a lot of research on the human microbiota, there is a considerable lack of understanding regarding the wide range of peptides that these microbial populations produce. Particularly noteworthy are the antibiotics that are uniquely produced by the human microbiome, especially by bacteria, to protect against invasive infections. This review seeks to fill this knowledge gap by providing a thorough understanding of various peptides, along with their in-depth biological importance in terms of human disorders. Advancements in genomics and the understanding of molecular mechanisms that control the interactions between microbiota and hosts have made it easier to find peptides that come from the human microbiome. We hope that this review will serve as a basis for developing new therapeutic approaches and personalized healthcare strategies. Additionally, it emphasizes the significance of these microbiota in the field of natural product discovery and development.

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Abdul Bari Shah

Abdul Bari Shah is a postdoctoral research associate at the Natural Products Research Institute, College of Pharmacy, Seoul National University (SNU), South Korea. In 2023, he earned his PhD in the field of organic and natural product chemistry from Gyeongsang National University, South Korea, under the supervision of Prof. Ki Hun Park. The focus of his work mostly involves the separation and identification of bioactive compounds produced by plants, fungi, and the human microbiota, as well as studying their biological functions. He was awarded the young pioneer research award twice for his exceptional performance during his research career.

Sang Hee Shim

Sang Hee Shim is a Professor at the Natural Products Research Institute, College of Pharmacy, at Seoul National University (SNU), Korea. She began her career as a post-doctoral researcher at the University of Iowa and the University of Illinois at Chicago after receiving her PhD from SNU in 2004. Then she started independent work at Yeungnam University in 2007 until she transferred to Duksung Women's University in 2015. In 2021, she joined SNU as a professor. Her research group mainly focuses on the discovery of bioactive compounds from endosymbiotic microorganisms. She has published over 100 SCI(E) research papers as of 2024.

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1 Introduction

Researchers worldwide have examined the complex relationship between the intestinal microbiome and human health due to the significant progresses in sequencing technologies over the past ten years.^1,2 The term “microbiota” has its roots around the past twenty years, when scientists noticed that various parts of the human body were home to several kinds of microbes, such as bacteria, yeasts, and viruses that coexisted symbiotically with the host and had a major impact on immunological response, physiological functions, and disease susceptibility.^3,4 At the same time, the functional potential and metabolic diversity of these microbial communities are reflected in the human microbiome, which includes the collective genetic material of the microbiota. At an early stage of development, humans establish symbiotic associations with these microorganisms. This assemblage is influenced by various factors including the environment, closeness to other humans and animals, food, genetics, and behavioral change,⁵ and in turn, these complex relationships between host genetics, environmental conditions, and the dynamics of microbial colonization have led to the amazing diversity and adaptability of the human microbiota and microbiome.⁶

Most of the complex microbial communities found in the human body are composed of bacteria, with members of well-known families, including Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, Proteobacteria, and Verrucomicrobia, inhabiting specific physiological niches. These microbes are present in the skin, oral cavity, respiratory system, gastrointestinal tract, and urogenital regions, among other locations. Fungi are less prevalent; however, they are crucial for microbial variety and functionality. Each possesses distinct features and functions within the human body. It is becoming more and more evident that how they participate in both healthy and diseased states emphasizes how crucial it is to comprehend their roles within the human microbiota.^4,7

The ability to recognize biosynthetic genes within bacterial genome sequences has been transformed by recent developments in genomic sequencing technology, which has made it easier to predict the chemical structures of a wide range of metabolites. This method, known as genome mining, has been shown to be an effective means of finding a wide spectrum of bioactive substances. Among the most important players in this process are the biosynthetic gene clusters (BGCs), which encode various regulatory elements and enzymes essential for coordinating the biosynthesis and ecological roles of secondary metabolites.^8,9 The production of secondary metabolites is fundamentally guided by genetic blueprints found in these clusters. Using 16S rRNA gene, sequencing has improved our ability to comprehend different bacterial species in microbiota samples.¹⁰ By linking this method with hypotheses derived from genome sequences and the existence of secondary metabolite clusters, we can speculate about the possible metabolic strength of these bacterial species. These integrated approaches offer significant insights into the varied metabolic characteristics and physiological functions of microbial communities occupying different ecological places. Besides these developments, new bioinformatic techniques that have recently drastically changed the field of natural product discovery play a crucial role in identifying novel metabolites from the vital reservoir of the human microbiota.

With the help of this advanced and broad knowledge, a wide range of naturally occurring substances linked to human health have been isolated from microorganisms. These compounds have a wide range of chemical structures that are comparable to those of bacteria found in both aquatic and terrestrial environments.^11,12 Among them are compounds that are essential mediators for interactions between different microbiological species and their hosts.^13,14 The human microbiota-derived peptides play a significant role in the controlling of many human disorders, from antimicrobial to anti-inflammatory, anticancer and from obesity to diabetes and mental disorders. In addition, these peptides significantly affect metabolism, many inflammation pathways, and gut–brain axis interactions. As an example, bacteriocin helps to keep the microbiota community together by preventing harmful bacteria from multiplying. In the event of dysbiosis, which has been associated with inflammatory bowel disorders (IBD), these peptides also keep the microbiota community balanced.^4,15

The primary objective of this review is to undertake a thorough investigation of peptides that come from the human microbiome. We aim to disclose the health potential and health challenges of the peptides that are derived from human microbiota, specifically bacteria by a thorough examination and synthesis through available literature. Our review starts with a discussion of the significance of the human microbiota. It then provides an extensive overview of the literature that is currently accessible on most of the peptides that are produced by these microbiota.

2 Methodology

All essential information regarding peptides originating from the human microbiome was gathered from the published literature. Research articles on human microbiota peptides were obtained from various scientific sources, including PubMed, the Web of Science, the American Chemical Society (ACS), the American Society of Microbiology (ASM), Google Scholar, and SciFinder. The process of selecting and evaluating publications for their relevance was carried out by considering their titles, abstracts, and keywords. The chemical structures were drawn using ChemDraw 22.2.0 (structure with less number of amino acids) and https://app.biorender.com/.

3 Human microbiota and microbiome are hosts of important peptides

The gastrointestinal tract (GIT), an ecosystem filled with over 100 trillion microorganisms, contains an incredible assortment of approximately 3 million genes.^16,17 Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia are the phyla with the most dominant bacterial populations. These occupants of the GIT participate in a variety of activities that benefit the host. These activities include the breakdown of vitamins and metabolites including bile acids, amino acids, and lipids. They also regulate pH, produce peptides, and influence several cell signaling pathways.^18–20 Metabolites are essential components of the human microbiome, serving different roles in sustaining health and affecting disease progression.^21,22 Metabolites, particularly those peptides in the gut, play a crucial role in host–microbe interactions. They alter the local environment and influence overall health. BGCs linked with metabolite biosynthesis provide significant information on the mechanisms behind their synthesis.^10,22–24

The oral cavity ranks second in hosting microbiota, comprising over 700 bacterial species. Oral microbiota demonstrates remarkable diversity in predicted protein activities compared to other body locations. The oral cavity comprises two types of sites for bacterial colonization: the hard and soft tissues of the teeth and the oral mucosa. These microbiota always experience significant alterations in composition and activity, mostly influenced by nutrition, pH variations, bacterial interactions, and genetic mutations that may lead to the emergence of new strains.^25,26 Moreover, the skin hosts a varied assortment of symbiotic bacteria that inhabit certain niches, which is essential for maintaining our health and provides an unexpected variety of additional benefits. The primary bacteria are Staphylococcus and Propionibacterium spp., which constitute a substantial component of the skin microbiota.²⁷

The human microbiota produces several types of secondary metabolites such as ribosomally synthesized and post-translationally modified peptides, including lantibiotics and bacteriocins, microcins and thiazole-/oxazole-modified microcins, and heat-stable enterotoxin. Moreover, they include the byproducts of amino acid metabolism, oligosaccharides, glycolipids, terpenoids, polyketides, and nonribosomal peptides. These many groups make up the metabolic profile of the human microbiota.^28,29 Although not all species within the human microbiota contribute to these substances, it is essential to thoroughly examine the other species that may yield novel bioactive compounds. The genomic loci consist of genes that encode enzymes responsible for the synthesis of various metabolites, providing a detailed plan for comprehending their production pathways. Scientists can examine BGCs to discover potential therapeutic targets for controlling metabolite production or to create probiotic strains with enhanced beneficial metabolite synthesis.^30,31

It is known that several kinds of bacteria in the human microbiome are very capable of synthesizing peptides. Firmicutes and Bacteroidetes are predominant bacterial phyla in the gut. They are known for their wide range of metabolic activities. Short-chain fatty acids (SCFAs) and peptides are produced mostly by Firmicutes, which include genera like Clostridium and Lactobacillus, whereas Bacteroidetes, which include Bacteroides, are involved in the breakdown of polysaccharides and the synthesis of SCFAs. Furthermore, it is well recognized that Actinobacteria, which are represented by genera such as Bifidobacterium, produce healthy metabolites including vitamins and SCFAs.^32–34 Most of the important peptides related to these groups of bacteria will be discussed in detail along with their in-depth biological role.

4 In-depth investigation of human microbiota-generated peptides and their significance in human disorders

A comprehensive analysis of the gut microbiota in a wide range of subjects, including humans and animals that have been treated with antibiotics, are germ-free, or are gnotobiotic, has revealed a strong connection between the gut microbiota and the development or advancement of several diseases. This link goes beyond a simple correlation, indicating a possible causal role of gut microbiota in the development of diseases. Various conditions such as non-alcoholic fatty liver disease, inflammatory bowel disease, allergies, obesity, Alzheimer's disease, Parkinson's disease, and depression have been linked or associated with gut microbiota. The complex relationship between gut microbiota and human health highlights the significant impact it has on disease development, emphasizing the need to comprehend its nuanced interaction with disease pathogenesis.^35,36 Undoubtedly, metabolites produced by essential components within the microbiota have the ability to treat these various disorders. The six phyla of bacteria, previously mentioned, play a major role in the production of peptides, which have an enormous effect on the pathophysiology of human diseases. However, there is still a lack of thorough knowledge on the particular taxa of bacteria that produced different peptides and the frequency of similar compounds in different bacterial species. The objective of this investigation is to thoroughly classify the variety of bacterial species that live in the human microbiota and outline their individual roles in the treating of many human disorders. With broad implications for both ecological science and medical research, this endeavor attempts to provide insightful understandings of the complex interactions that shape microbial ecology by clarifying complex relationships between microbial communities and their metabolic outputs.

4.1 Critical role of peptides generated from Firmicutes (Bacillota) in human disorders

Firmicutes and Bacteroidetes are two major bacterial phyla that make up the majority of the human gut microbiota. They account for more than 90% of the overall microbial population.³⁷ Even with such a strong makeup, which is dominated by these phyla, the gut microbiota is remarkably resilient to short-term disturbances and can quickly return to its initial state.¹⁶ Different peptides produced by Firmicutes can significantly contribute to the physiology and health of a host. Firmicutes are a broad category of bacteria that include genera Bacillus, Lactobacillus, Clostridium, Ruminococcus, and Enterococcus, among others.^1,32 The human gut microbiota produces a wide range of bioactive peptides, and these bacteria are well known for their adaptability in metabolism.^18,38

4.1.1 Antimicrobial, anti-inflammatory and anticancer peptides along with other biological activities and their mechanisms of action. Antimicrobial peptides refer to a class of antibiotics that primarily focus on the cell wall of Gram-positive bacteria.³⁹ These peptides have the ability to interfere with the formation of biofilms at any stage of their development. The primary functions of these antimicrobial peptides encompass antibacterial, antifungal, antiviral, and immunomodulatory activities. Antimicrobial peptides, due to their mechanisms of action, can effectively overcome various limitations associated with the use of traditional antimicrobials. These limitations include the growing problem of multidrug resistance, which poses a significant threat to public health, and raises concerns regarding potential systemic toxicity and overall effectiveness.^40,41 Additionally, some peptides found in the human microbiome have a crucial function in reducing inflammation and fighting against cancer. In the following text we will carefully highlight the biological role of most of the peptides derived from the human microbiota, especially bacteria.
4.1.1.1 Bioactive peptides from Bacillus and Lactobacillus and their biological roles. Bacillus and Lactobacillus are both found in the human microbiota, contributing significantly to the secretion of metabolites and playing a profound biological role. The number of peptides that have been isolated and characterised so far from Lactobacillus is significantly greater than that from Bacillus. For example, two peptides, Trn-α and Trn-β called thuricin CD, were extracted from the human fecal isolate Bacillus thuringiensis DPC 6431 The amino acid sequence for Trn-β consists of 49 amino acids (molecular mass = 2763), while Trn-α comprises 47 amino acids (molecular mass = 2861), demonstrating 45.3% sequence similarity and 39.6% identity, with both sequences containing three thioether linkages. The structure comprises six cycles of amino acids situated between Cys9 and Thr25, Cys5 and Thr25, and Cys13 and Ser21 in Trn-α, along with Cys9 and Ala25, Cys5 and Tyr28, and Cys13 and Thr21 in Trn-β. Subsequent NMR calculations validated the distinct D and L stereochemistry, leading to the formation of LLD isomers. These peptides have the ability to eliminate a broad spectrum of Clostridioides difficile, including ribotypes that are typically linked to Clostridium difficile-associated disease (CDAD).^42,43 CDAD is a severe infection of the colon caused by the bacteria Clostridioides difficile, which typically affects people whose normal intestinal bacteria have been disturbed, generally due to recent antibiotic usage. The spectrum of this condition encompasses mild cases of diarrhoea to severe cases of sepsis and potentially fatal outcomes, with mortality rates reaching as high as 25% in vulnerable elderly individuals.⁴⁴ An investigation employing flow cytometry and culture-dependent tests revealed that both Trnα and Trnβ induce membrane collapse, resulting in reduced cell size and granularity. The lytic activity occurs when thuricin CD peptides are inserted into target cells, causing the membrane to depolarize and resulting in cell death.⁴⁵ One study demonstrated that thuricin CD exhibits activity at low doses when both peptides are present. A nanoformulation based on anionic lipids shows potential as a novel method for delivering thuricin CD locally through the oral route.⁴⁶ Thuricin CD and several antibiotics (tigecycline, vancomycin, teicoplanin, rifampicin, and nitazoxanide) were tested on Clostridium difficile strains in biofilms and planktonic cells. The results demonstrated that Clostridium difficile strains differed in biofilm formation and antibiotic sensitivity. These findings offer new Clostridium difficile treatment techniques since strong biofilms in some strains can increase antibiotic resistance and infection recurrence.⁴⁷ A comprising effect of fidaxomicin, a narrow spectrum antibiotic, on the human gut microbiome with thuricin CD and vancomycin and nisin was studied, demonstrating that thuricin CD was specific to Clostridium difficile and some Bacillus spp., with lower MICs for few other strains tested.⁴⁸Fig. 1 represents a simple approach of thuricin CD isolation and its activity.

Fig. 1 Trn-α and Trn-β isolated from Bacillus thuringiensis DPC 6431 as antibacterial agents against Clostridioides difficile (similar approach can be applied to most other bacterial metabolites).

Conversely, lactobacilli, a major group of bacteria in the human body, have established themselves in several regions, particularly the digestive system, oral cavity, and female vaginal tract. They make a substantial contribution to compositions of metabolites in these places. Numerous metabolites generated by Lactobacillus, including organic acids, carboxylic acids, phenolic acids, cyclic dipeptides, hydrogen peroxide, reuterin, various proteinaceous compounds, and diverse antifungal substances, have been investigated for their potential to inhibit a wide range of fungal species.^49,50 Itol et al. have studied a set of 73 strains of Lactobacillus acidophilus, in addition to one strain of Lactobacillus reuteri. The strains were obtained from human fecal samples and subsequently assessed for their ability to generate antimicrobial compounds against 16 strains that encompassed six distinct type of food-borne enteric pathogenic bacteria. Several strains of Lactobacillus gasseri exhibited notable inhibitory effects against the microorganisms that were tested. Gassericin A (1), produced by Lactobacillus gasseri LA39 isolated from human infant/adult feces on modified Lactobacillus selective agar, was found to be a powerful bacteriocin that could effectively kill bacteria without causing cell death,⁵¹ and gassericin T was also produced by Lactobacillus gasseri SBT 2055 isolated from human feces that displayed antibacterial activities.⁵² These bacteriocins have excellent thermal stability, favourable pH resistance, and potent bactericidal activity against numerous Gram-positive bacteria, particularly lactic acid bacteria. It is anticipated that they would serve as efficient food preservatives. Gassericins exhibit a wider range of antibacterial activities than those of nisin A. They are capable of inhibiting the growth of Gram-negative isolates when glycine is added. They can be effectively generated through the cultivation process in a food-grade medium utilising cheese whey, proteose–peptone, and surfactant yolk lecithin. The efficacy of gassericin A and glycine as preservatives was confirmed by demonstrating their ability to suppress the growth of microorganisms in custard creams.⁵³ Furthermore, Lactobacillus gasseri SF1109 yielded a peptide of small size known as EFV12. This peptide exhibits the ability to bind to lipopolysaccharides (LPS) and efficiently mitigate their inflammatory effects through the inhibition of LPS interaction with Toll-like receptor 4. Consequently, it interferes with multiple signalling pathways, including the extracellular signal-regulated kinase, p38, and Jun N-terminal kinase mitogen-activated protein kinase pathways.^54,55

Reutericin 6 with lytic activity was purified from Lactobacillus reuteri LA6b⁵⁶ (reutericin 6 was the original name given to gasserinin A when it was initially reported in 1991 (ref. 57)). Reutericin 6 isolated from Lactobacillus reuteri LA 6 displayed antimicrobial activity against a range of bacteria that contain Lactobacillus acidophilus JCM 2125 and Lactobacillus delbrueckii (with many other strains).⁵⁸ Lactocillin (2), a member of the thiopeptides class, has been successfully isolated and structurally characterized from Lactobacillus gasseri JV-V03, which exhibits antibiotic action towards vaginal infections within the low-to-mid nanomolar range. Nevertheless, it does not demonstrate such efficacy against vaginal commensals. It is worth noting that LFF571, another thiopeptide similar to Lactocillin, is currently undergoing phase II clinical studies.⁵⁹

The investigation of the peptidome produced by Lactobacillus fermentum was undertaken by Pavlova et al. with the aim of identifying peptides that may have antibacterial effects. The Lactobacillus fermentum HF-D1, a new strain, exhibits the ability to generate antimicrobial peptides that demonstrate significant efficacy against Serratia marcescens and Pseudomonas aeruginosa. The active fraction was subjected to mass spectrometry analysis, followed by in silico prediction of antimicrobial peptides. As a result, a linear peptide sequence has been discovered as (VGAVAFGPVGAVVGGLASGFTGKQT). In addition, they discover a collection of cyclic peptides that have a high prediction score. One of them is an Epidermidin-like peptide, which is recognized for its antibacterial properties.⁶⁰Lactobacillus acidophilus M46 is responsible for the production of acidocin B (3), a new bacteriocin that exhibits activities against many bacterial strains including Listeria monocytogenes, Clostridium sporogenes, Brochothrix thermosphacta, Lactobacillus fermentum, andLactobacillus delbrueckii subsp. Bulgaricus.⁶¹ The isolation and optimization of production of acidocin B were done by Brink et al., in which they find out that this peptide is heat stable and sensitive to trypsin and their in-depth antimicrobial study and mechanism reveal that it shows more inhibitory power to clostridia as compared to other lactobacilli species.⁶² Acidocin A, which is also a bacteriocin extracted from Lactobacillus acidophilus TK9201, display antimicrobial activity against lactic acid bacteria and also food-borne bacteria.⁶³ Moreover, Acidocin A was administered to human erythrocytes (hRBC) obtained from two participants for testing purposes. At a dosage of 128 μM or below, it caused the destruction of only 3% of human red blood cells. Their toxic effect along with avicin A was assessed in primary human cells PBMCs and THP-1. Both acidocin A and melittin (control) but not avicin A, exhibited toxicity towards both cell lines, however PBMCs have shown more sensitivity to the peptide effects. Furthermore, the intensity of the cytotoxic impact decreased as the duration of cell incubation with resazurin extended from 2 to 24 hours. The observed harmful effects were likely attributed to a reduction in metabolic activity and cellular proliferation. It was also found out that acidocin A along with others enhanced the synthesis of inflammatory chemokines.⁶⁴ The structures of peptides (1–3) are presented in Fig. 2. The identification of acidocin J1132 (alpha and beta 4) was achieved in the Lactobacillus acidophilus strain JCM1132. This demonstrates bactericidal characteristics and interferes with the membrane potential and pH gradient in vulnerable cells, thereby affecting proton motive force-dependent processes including amino acid transfer. The acidocin J1132 compound also elicits the expulsion of previously accumulated amino acids, which were first absorbed via a unidirectional transport route driven by ATP. This peptide is associated with alpha and beta components, with the beta component having an additional glycine residue and both components have inhibitory activities, with the increase in activity due to their complementary action.^65,66 A bacteriocin-like peptide called rhamnosin A (5) was isolated from Lactobacillus rhamnosus 68. Rhamnosin A demonstrated inhibitory effects on Micrococcus lysodeikticus ATCC 4698; however, it did not exhibit any inhibitory effects on Lactobacillus plantarum 8014 or Lactobacillus plantarum 39 268. The inhibitory activity against Micrococcus lysodeikticus was observed at concentrations that demonstrated bacteriostatic effects rather than bacteriolytic or bactericidal effects. Furthermore, it maintained its biological functionality even after being subjected to heat treatment at 95 degrees Celsius for 30 minutes. However, it was susceptible to degradation by the proteolytic enzymes pepsin and trypsin.⁶⁷ The investigation focused on the anticancer capabilities of recombinant bacteriocins, rhamnosin and lysostaphin (isolated from Staphylococcus simulans), which were generated in Escherichia coli, demonstrating a dose-dependent inhibition of cancer cell lines (CCA) while exhibiting lower toxicity towards normal cholangiocyte cells. Rhamnosin and lysostaphin displayed comparable or superior growth-inhibitory effects on gemcitabine-resistant cell lines compared to their parental equivalents. The simultaneous use of bacteriocins resulted in the suppression of cell growth and the promotion of cell apoptosis in both normal and gemcitabine-resistant cells, partially due to the upregulation of proapoptotic genes.⁶⁸ A bactericidal and strongly hydrophobic bacteriocin amylovorin L471 also known as lactobin A (6) was isolated from Lactobacillus amylovorus DCE 471, which shared significant homologies with amino acid lactacin X, one of the two bactericidal peptides produced by Lactobacillus johnsonii VPI11088.⁶⁹ The amyloyrin L471, which was later named amyloyrin L,⁷⁰ exhibited no activity against the Gram-negative opportunistic pathogen Pseudomonas aeruginosa when used alone. However, it demonstrated synergistic inhibitory activity when combined with the peptide antibiotic colistin, as well as with bacteriocins pyocins S1 and S2 of Pseudomonas aeruginosa.⁷¹ The structures of peptides (4–6) are presented in Fig. 3.

Fig. 2 Structures of gassericin A (1), lactocillin (2), and acidocin B (3).

Fig. 3 Structures of acidocin J1132 (alpha and beta 4), rhamnosin A (5), and lactobin A (6).

A bacteriocin known as plantaricin C (7), having a 27-amino-acid sequence had one dehydroalanine, one lanthionine, and three beta-methyl-lanthionine residues. The core area of plantaricin C has a charge distribution that is suitable for an amphipathic alpha-helix. This allows the plantaricin C to be incorporated into the membrane matrix of susceptible organisms. Due to such property, it targets the cytoplasmic membrane permeability barrier, which interferes with processes that depend on the transmembrane electrochemical gradient (Δp) by disrupting it. Moreover, it causes the release of glutamate, CF, and ATP, suggesting that plantaricin C is a pore-forming bacteriocin.^72,73 In order to see the mechanism, one study found out that this lantibiotic exhibits structural characteristics of both type A lantibiotic nisin and type B lantibiotic mersacidin. Lipid II was discovered to have a crucial function in the antibacterial activity of plantaricin C, specifically in pore formation. Plantaricin C was discovered to be a highly effective inhibitor of lipid II synthesis and the FemX reaction. These processes were hindered by the creation of a complex between plantaricin C and either lipid I or lipid II, leading to the inhibition of cell wall synthesis. This antimicrobial peptide is distinct because it contains lanthionine and β-methyllanthionine residues. These residues are added after the peptide is synthesised by specialised enzymes expressed by the lantibiotic operons.⁷⁴ Plantaricin A (8) also enhances the antibiotic effectiveness through increasing the bacterial permeability. Another analogue, plantaricin A1, was used to improve the capacity of such peptide permeability in the membrane. OP4 (analogue) exhibited superior penetration, lower cytotoxicity, and a greater therapeutic index. Furthermore, it inhibited the development of antibiotic resistance in E. coli cells that were subjected continuously to sublethal concentrations doses of erythromycin and ciprofloxacin. OP4 demonstrated enhanced efficacy against E. coli and alleviated inflammation in in vivo experiments. The study determined that plantaricin A1 analogues, specifically OP4, decrease inherent antibiotic resistance in Gram-negative bacteria and enhance hydrophobic antibiotic susceptibility.⁷⁵ The plantaricins EF (9) and JK (10) has been isolated from Lactobacillus plantarum C11, exhibiting strain-specific antagonistic activity at nanomolar concentrations when plantaricin E and plantaricin F are combined, as well as when plantaricin J and plantaricin K are combined.⁷⁶ These peptides are thought to have an amphiphilic structure, which is believed to play a role in creating pores. Both plantaricin EF and plantaricin JK, which are complimentary peptides, interact with one another due to the fact that the simultaneous addition of both peptides synergistically stimulated the production of their α-helical structure in the presence of dioleoylphosphatidyl-glycerol liposomes. These peptides produce pores in the target membranes that have varying degrees of ion selectivity. The use of these bacteriocins in conjunction with one another and in a complimentary manner ensures that target cells are eliminated effectively.^77,78 These bacteriocins were also recovered from a human faecal isolation of Lactobacillus plantarum LbM2a, which exhibited a broad antibacterial spectrum in addition to a high degree of stability to various conditions.⁷⁹ One of the study identifies a potential membrane protein receptor for the bacteriocin plantaricin JK, by comparing Illumina sequence reads from resistant mutants to a wild-type Weissella viridescens genome, demonstrating that APC superfamily transporter is likely to serve as a target for plantaricin JK on sensitive cells.⁸⁰ There have been numerous more plantaricins found to originate from this particular bacterium. In general, the primary focus of these plantaricins is on treating conditions that are caused by pathogenic bacteria, irritable bowel syndrome (IBS) and urinary tract infections (UTI).⁸¹ The structures of peptides (7–10) are presented in Fig. 4.

Fig. 4 Structures of plantaricin C (7), plantaricin A (8), plantaricin EF (9), and plantaricin JK (10).

The cytotoxic activity of synthesised plantaricin A was investigated. The experimental results demonstrated that the application of 25 μM plantaricin A at 20 °C resulted in a significant 75% drop in cell viability. In contrast, when the treatment was conducted at 37 °C, the cell viability was reduced by 55%. Both apoptosis and necrosis were detected. Treatment with plantaricin A also led to an increase in the intracellular levels of caspase-3 in the Jurkat cell line. The study investigated the impact of the lipid composition of liposomes on the interaction between plantaricin A and liposomal membranes.⁸² Further, two things were demonstrated, first, that plantaricin A produces amyloid-like fibrils upon binding with negatively charged phospholipids such as phosphatidylserine; and second, that it easily leaked the fluorescent dye carboxyfluorescein from liposomes that contained negatively charged phospholipids. This suggests that the target cell membrane's negatively charged lipids may enhance plantaricin A attachment and localise it to the membrane.⁸³ The effects of plantaricin A on anterior pituitary cells in rats were also investigated. Within 5 seconds of exposure to 10–100 μM plantaricin A, cancerous cells exhibited substantial permeabilization. The resistance dropped to a fraction of its original value as the membrane depolarized to almost 0 mV. A nonchiral mechanism was indicated by the fact that the efficacy of the peptide was similar in its D and L forms. Plantaricin A shows that it distinguishes between membrane leaflets and plasma membranes because it was insensitive to inside-out patches and main cultures of normal rat anterior pituitary cells.⁸⁴ Further it was shown that how well the cationic peptide pheromone plantaricin A permeates clonal rat anterior pituitary cells (GH4 cells). While the results demonstrate that GH4 cells exhibit a high level of sensitivity to plantaricin A, this sensitivity is mitigated in solutions that partially counteract the negative surface charge of the cell. According to the research, plantaricin A must first bind to glycosylated membrane proteins electrostatically before it can bind to membrane phospholipids.⁸⁵ Eukaryotic cells are protected from plasma membrane damage by the binding of positively charged bacteriocins (nisin A, plantaricin C, and pediocin PA-1/AcH) to the negatively charged glycosaminoglycan sulphate residues. Heparin, which likewise reduces the susceptibility of Lactococcus lactis to nisin A, can partially reverse this effect.⁸⁶ Along with this, Lactobacillus plantarum strains are recognised for their anti-inflammatory effects, presence in the human gastrointestinal system, immunomodulatory capabilities, and potential medicinal applications. Upon isolation of peptides, the strain Lactobacillus plantarum WCFS1 has been found to produce four pyro dipeptides (pyro-phenylalanine, pyro-leucine, pyro-isoleucine, and pyro-tryptophan). The immunomodulatory characteristics of these compounds were examined by directly administering it to C57BL/6 mice in vivo, resulting in a reduction in the production of the pro-inflammatory cytokine interferon (IFN)-gamma, which is known to have a crucial function in maintaining immunological balance in the gastrointestinal tract.⁸⁷

Another bacteriocin lactacin F (11) produced by Lactobacillus johnsonii also demonstrates bactericidal properties against Lactobacillus delbrueckii, Lactobacillus helveticus, and Enterococcus faecalis.^65,88 Lactacin F was first derived from Lactobacillus acidophilus 11 088 (NCK88). It is characterized as a heat-resistant protein that has inhibitory effects on other lactobacilli and Enterococcus faecalis.⁸⁹ Lactacin F activity, which is defined by its bactericidal action on Lactobacillus delbrueckii, is dependent on the expression of two genes, namely lafA and lafX. Actually, two peptides, lactacin A (57 amino acids) and LafX (48 amino acids), make up lactacin F.^90,91Lactobacillus helveticus 481 synthesized an antimicrobial compound known as helveticin J that effectively inhibited the growth of five closely related species, namely Lactobacillus helveticus 1846 and 1244, Lactobacillus bulgaricus 1373 and 1489, and Lactobacillus lactis 970. This peptide exhibited activity at a neutral pH, was susceptible to proteolytic enzymes and heat, and displayed a bactericidal mechanism of action.⁹² ABP-118 (12), produced by Lactobacillus salivarius subsp. salivarius UCC118, a strain isolated from the ileal-caecal area of the human gastrointestinal system, is a tiny heat-stable bacteriocin consisting of abp118alpha and abp118beta. It is noteworthy that Abp118alpha had antibacterial action, while Abp118beta exerted an improved antimicrobial effect. The gene abpIM, which provides strain UCC118 with immunity to ABP-118, has been found to be located downstream of the abp118beta gene.⁹³ Along with genome analysis, the bacteriocin activity and the causative genes, which are homologs of salivaricin ABP-118 in Lactobacillus salivarius UCC118, have been verified.⁹⁴ The structures of peptides (11–12) are presented in Fig. 5.

Fig. 5 Structures of lactacin F (11) and ABP-118 (12).

4.1.1.2 Bioactive peptides from Clostridium and Enterococcus and their biological role. Clostridium is well acknowledged as a prominent gastrointestinal colonizer, frequently observed in individuals of all age groups, including infants and adults. Clostridium has a significant degree of genetic diversity, positioning it as the most extensive genus within the realm of anaerobic spore formation. Several significant infectious microbes including the agents causing botulism and tetanus in humans are found within this genus. In the past, Clostridium included a crucial pathogen that causes diarrhea, known as Clostridioides difficile. However, in 2016, it was reclassified into the Clostridioides genus.^95–97 In the course of peptides, boticin B (13) is a bacteriocin that exhibits thermal stability and is synthesized by strain 213B of Clostridium botulinum. It demonstrates inhibitory properties against a range of strains of Clostridium botulinum and other closely related clostridia.⁹⁸ The lytic activity of this bacteriocin has been reported in 1972, but the original article is in Japanese language and we are unable to review further details.⁹⁹Clostridium beijerinckii ATCC 25752 produces a prepeptide comprising 72 amino acids, which undergoes processing to become a circular peptide comprised of 69 amino acid residues known as circularin A (14). Clostridium tyrobutyricum ADRIAT 932, in contrast, synthesizes a bacteriocin known as closticin 574. This bacteriocin is an 82-amino-acid peptide. In order to test this, twelve clostridial strains were analyzed to determine their ability to inhibit the growth of Clostridium tyrobutyricum B570, a widely recognized bacterium responsible for cheese spoilage, which exhibited the highest level of activity.¹⁰⁰ Liu et al. were able to successfully carry out cloning, and heterologous expression system for clostridial circularin A and were able to produce this circular peptide in Lactococcus lactis NZ9000 successfully. Furthermore, by overlay activity experiment, the responsible strain was able to exert varied activities against various bacteria.¹⁰¹ The structures of peptides (13–14) are presented in Fig. 6.

Fig. 6 Structures of boticin B (13) and circularin A (14).

Enterococci belong to the class of lactic acid bacteria and normally present in the gastrointestinal tract of humans and animals.^102,103Enterococcus villorum SB2 isolated from female vagina displayed the presence of many metabolites including flavonoids, terpenoids, O-methylganoderic acid, and indole derivatives produced by tryptophan metabolism, antimicrobial compounds (fortimicin A) and fatty acids. In addition, several other metabolites were documented, including glutamate amino acid analogues (L-theanine), galactose, lactate, ketohexose deoxy sugar, acetylated glycerols, dipeptides (threoninyl-proline, valyl-glycine), and gutyrolactones; however, a peptide with several amino acids was not detached.¹⁰⁴ A bacteriocin named bacteriocin 43 (15) was isolated from Enterococcus faecium. In such study, 636 vancomycin-resistant Enterococcus faecium isolates obtained between 1994 and 1999 from the Medical School Hospital of the University of Michigan underwent testing for bacteriocin production. Of which 44% exhibited bacteriocin production, 21 strains also showed activity against Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae, Enterococcus durans, and Listeria monocytogenes.¹⁰⁵

In a similar way, bacteriocin 32 was isolated from Enterococcus faecalis and demonstrated activity against Enterococcus faecium, Enterococcus hirae, and Enterococcus durans. However, it did not exhibit any activity against Listeria monocytogenes.¹⁰⁶ Another bacteriocin in the same series, bacteriocin 31 (16), was found in Enterococcus faecalis, which exhibits activity against Enterococcus hirae 9790, Enterococcus faecium, and Listeria monocytogenes,¹⁰⁷ and bacteriocin RC714 (17) was also found in Enterococcus faecalis.¹⁰⁸ These bacteriocins typically exhibit activities against their closely related genus, which is often responsible for causing urinary tract infections, meningitis, intra-abdominal, and wound infections.¹⁰⁹Streptococcus faecalis S-48 (Streptococcus faecalis also called Enterococcus faecalis) resulted in the production of a broad spectrum antibiotic, called AS-48 (18), which shows activities against many Gram-negative and Gram-positive bacteria.¹¹⁰ Gram-negative bacteria demonstrate higher resistance and exhibit a bacteriolytic action, potentially associated with initial lesions. In addition, the resistance is connected to the cell wall due to the fact that E. coli protoplasts and yeast resistance lead to an amplified sensitivity of Saccharomyces cerevisiae 3.2.¹¹¹ Significant sensitivity to AS-48 was demonstrated by the bacterial strains Corynebacterium, Mycobacterium, and Nocardia, all of which contain mycolic acid in their cell walls. Nevertheless, after treatment with bacteriocin, none of them exhibited any signs of bacteriolysis. When bacteriocin was added, none of the Gram-positive bacteria, including micrococcus and Staphylococcus species, were able to be lysed. These bacteria were less susceptible than the Gram-positive bacteria. Moreover, Escherichia coli K-12 is susceptible to the bactericidal effects of this peptide; however, it does not exhibit bacteriolytic properties. As a whole, this peptide has been studied well to show both bactericidal action and bacteriolytic action.¹¹² Cytolysin, a peptide toxin derived from Enterococcus faecalis, has attracted attention due to its ability to augment enterococcal virulence in infection models. It is secreted by both pathogenic and non-pathogenic Gram-positive bacteria. Furthermore, epidemiological investigations have linked cytolysin to patient mortality. Cytolysin is an exceptional example of a molecule that demonstrates dual activities, functioning as both an antibiotic and a catalyst for its own synthesis. The process of invasion is facilitated through the induction of macrophage and neutrophil lysis, resulting in a reduction of host immunity. The efficacy of this highly durable toxin extends to a wide range of creatures, encompassing prokaryotes, humans, and even invertebrates.^113,114 Cytolysins are a type of pore-forming toxins (PFT) that are among the most numerous types of toxins. They are mostly produced as water-soluble monomers that attach to the lipid membrane of eukaryotic cells. This binding causes the passage of molecules from inside the cell to the outside, leading to the lysis of the host cell.¹¹⁵ The structures of peptides (15–18) are presented in Fig. 7.

Fig. 7 Structures of bacteriocin 43 (15), bacteriocin 31 (16), bacteriocin RC714 (17), and AS-48 (18).

4.1.1.3 Bioactive peptides from Ruminococcus and Staphylococcus and their biological roles. The genus Ruminococcus comprises strictly anaerobic, Gram-positive, non-motile cocci that do not form endospores and depend on fermentable carbohydrates for their growth. Ruminococcus species are prevalent constituents of the core gut microbiome in a significant portion of the human population.^116–118 In the context of peptides, Ruminococcus gnavus, an important part of the human microbiota, has been identified as the source of ruminococcin C, a sactipeptide distinguished by the presence of four Cα-thioether bridges in the L configuration. The antimicrobial activity of ruminococcin C is mainly because of the presence of thioether bridges and elimination of a leader peptide. Ruminococcin C is classified as a ribosomally synthesized and post-translationally modified peptide (RiPP) and demonstrates significant efficacy against the human pathogen Clostridium perfringens.¹¹⁹ The human commensal Ruminococcus gnavus E1 produced this peptide in vivo for the first time.¹²⁰ A specific variant ruminococcin C1 (19) (out of C1–C5) of ruminococcin C was obtained in vivo by Chiumento et al. Ruminococcin C1 exhibits post-translational changes facilitated by a particular sactisynthase enzyme, resulting in the formation of a thioether network that gives rise to a double-hairpin folding structure. This structural characteristic is essential for its biological functionality. Ruminococcin C1 exhibits antibacterial properties against pathogenic clostridia and multidrug-resistant strains, while maintaining non-toxicity towards eukaryotic cells, which renders it a highly interesting option for therapeutic development.¹²¹ As Ruminococcus gnavus E1 produces five sactipeptides, which are designated as Ruminococcins C1 to C5, these sactipeptides are co-expressed with two radical S-adenosyl-L-methionine (SAM) maturations. With the exception of Mc2, all isoforms exhibit antibacterial activity within the same range, while C2 is solely active against eukaryotic cells. There was no observed synergistic impact between different isoforms. However, the combination of C1 with traditional antibiotics could potentially serve as a therapeutic approach against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.¹²²

A total of 14 bacterial strains, derived from a variety of human fecal samples, were identified as exhibiters of a trypsin-dependent antimicrobial compound that demonstrates efficacy against Clostridium perfringens, which were classified as members of species such as Ruminococcus gnavus,Clostridium nexile, and Ruminococcus hansenii, or some others. The isolation of ruminococcin A (20) has been conducted from Ruminococcus gnavus, and it has been shown that seven other strains displayed comparable properties.¹²³ An N-acylated dipeptide aldehyde called ruminopeptin (21) has been predicated by a computational approach with in vitro biochemical characterization of biosynthetic enzymes from Ruminococcus bromii, the compound then synthesized, which inhibited Staphylococcus aureus endoproteinase GluC (SspA/V8 protease).¹²⁴ The structures of peptides (19–21) are shown in Fig. 8. The genus Staphylococcus has a wide array of species that are frequently observed inhabiting Staphylococci. They are widely acknowledged as important components of the human microbiome due to their extensive application on these both niches. One of the most prominent and thoroughly researched species in this category is Staphylococcus aureus. This particular species is characterized by its coagulase-positive nature and is recognized as an opportunistic human pathogen. It can shift from a commensal state to a pathogenic state, resulting in various illnesses.^125–128 Epilancin 15X (22), a lantibiotic, has been detected in Staphylococcus epidermidis from wound injury using High-Resolution Nuclear Magnetic Resonance Spectroscopy and Tandem Mass Spectrometry. Epilancin 15X exhibits three lanthionine ring structures, eleven post-translationally changed amino acids, and a hydroxy-propionyl N-terminal moiety. The structure of epilancin 15X is somewhat similar to epilancin K7 (23), having a similar mode of action.¹²⁹ Epilancin K7 has been reported in Staphylococcus epidermidis K7, the structure of which was determined by NMR spectroscopy and is a lantibiotic bacteriocin.^130,131 An effective self-resistance mechanism is shown by epilancin 15X, which demonstrates a powerful action against staphylococci. The structure of this lantibiotic is rather straightforward in comparison to that of other lantibiotics; nevertheless, it does contain an uncommon N-terminal D-lactate group. This group has the potential to be engineered into novel lantibiotics that exhibit additional antibacterial activities.¹³² It eradicates Staphylococcus carnosus and Bacillus subtilis by causing disruption to their membranes. The conservation of residues and dehydroamino acids in epilancin 15X was shown to be essential for its bioactivity, whereas the N-terminal lactyl group exhibits tolerance towards modifications. It has a detrimental impact on the process of fatty acid synthesis, RNA translation, and DNA replication, while not influencing the formation of the cell wall. Therefore, it was determined that this compound has the ability to elicit leakage from model membrane vesicles that contain negatively charged lipids in a manner regardless of lipid II.¹³³ In the most recent study, the mechanism of action of epilancin 15X was examined by dissipating the membrane potential of intact Staphylococcus simulans cells. Antibiotic treatment decreased epilancin 15X membrane depolarization effects, and disrupting the lipid II cycle in intact bacteria led to a decrease in its activity.¹³⁴Staphylococcus epidermidis Tu 3298 produces an important peptide antibiotic epidermin (24) that is synthesized in the ribosome through a precursor protein.¹³⁵ Gallidermin (25), derived from Staphylococcus gallinarum, is classified as a lantibiotic and exhibits structural similarities to epidermin. However, it possesses unique sources and displays particular antibacterial activities. They displayed antimicrobial against many Gram-positive pathogenic bacteria. The mode of action of both lantibiotics is similar to that of nisin. They interact with I, II, III (undecaprenol-pyrophosphate-N-acetyl-glucosamine), and IV (undecaprenol-pyrophosphate-N-acetyl-glucosamine-N-acetyl-mannosamine), thereby inhibiting not only murein but also wall teichoic acid manufacturing. Type A lantibiotics primarily kill bacteria by permeabilizing the membrane. However, only nisin and epidermin can form a complex with [¹⁴C]-lipid II, which is incorporated into carboxyfluorescein-loaded liposomes made of phosphatidylcholine and cholesterol.^136–138 The structures of peptides (22–25) are shown in Fig. 9.

Fig. 8 Structures of ruminococcin C1 (19), ruminococcin A (20), and ruminopeptin (21).

Fig. 9 Structures of epilancin 15X (22), epilancin K7 (23), epidermin (24), and gallidermin (25).

Epidermin along with pep5 which is also found in Staphylococcus epidermidis exhibited activity against clinical strains of Staphylococcus epidermidis and Staphylococcus aureus that were isolated from catheter-related infections. This activity was observed at a concentration of 640 activity units per ml.¹³⁹ The most recent study demonstrates that the pep5-producing strain exhibits efficacy against Staphylococcus aureus, and its entire sequence was identified for the first time. The study also discovered that the antibacterial action of nisin, nukacin, and pep5 (26) (Fig. 10) is dependent on respiratory constancy, which is controlled by two-component regulatory mechanisms.¹⁴⁰

Fig. 10 Structure of pep5 (26).

Epidermin also show synergistic effects with staphylolysin LasA A against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.¹⁴¹Staphylococcus epidermidis BN 280 leads to the extraction of a comparable peptide known as epicidin 280 (27). Epicidin 280 was shown to have a 75% similarity to pep5 based on amino acid sequence analysis.¹⁴² Epidermicin NI01 (28), an antimicrobial peptide is also produced by Staphylococcus epidermidis 224, is highly cationic, hydrophobic, and plasmid encoded. It exhibits potent antimicrobial activity against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), enterococci, and biofilm-forming Staphylococcus epidermidis strains.¹⁴³ One study found that single application of topical epidermicin NI01 was equally effective as twice daily administration of mupirocin for 3 days in eliminating MRSA from the nasal passages of cotton rats.¹⁴⁴ The structures of peptides (27–28) are displayed in Fig. 11.

Fig. 11 Structures of epicidin 280 (27) and epidermicin NI01 (28).

Staphylococcal genomes often encode epilancin A37 (29), an antibiotic that enters the cytoplasm of Corynebacteria via a largely transmembrane-potential-driven uptake that does not disrupt cell membrane function. The antibacterial activity of epilancin is dependent on the production of intracellular membrane vesicles, which this peptide promotes upon intracellular aggregation.¹⁴⁵ Two bacteriocin-producing genotypes of Staphylococcus epidermidis, KSE56 and KSE650, were identified in 150 isolates from the oral cavities of 287 volunteers. The epidermin-harboring plasmid pEpi56 and the nukacin IVK45-like-harboring plasmid pNuk650 were confirmed by the complete genome sequences. The amino acid sequence of epidermin from KSE56 was identical to that of previous reports; however, the genes related to epidermin synthesis were partially different. The prepeptide amino acid sequences of nukacin KSE650 (30) and IVK45 exhibited a single mismatch; however, the mature peptides were identical. In comparison to pIVK45, pNuk650 was larger and contained seven ORFs. The study observed distinct antibacterial activity profiles against different cutaneous and oral microorganisms.¹⁴⁶ Most specifically, it exerts antibacterial activity against nasal members of the Actinobacteria, Proteobacteria, and Firmicutes.¹⁴⁷

Staphylococcus lugdunensis strains have been recognized as synthesizers of lugdunin (31) (first reported nonribosomally synthesized antibiotic from human microbiomes), an exclusive cyclic peptide antibiotic that encompasses thiazolidine. It demonstrates bactericidal activity against important infections, demonstrates effectiveness in animal models, and displays a decreased propensity to create resistance in Staphylococcus aureus.¹⁴⁸ Subsequently, the same group conducted more research on this peptide, discovering that prior administration of lugdunin in conjunction with components generated from the microbiota resulted in a substantial decrease in Staphylococcus aureus colonisation in both primary human keratinocytes and mouse skin. Furthermore, it enhanced the production and secretion of LL-37 and CXCL8/MIP-2 in these cells, thereby attracting monocytes and neutrophils in living organisms. In addition, it successfully eliminated Staphylococcus aureus by combining the antibacterial effects of LL-37 with dermcidin-derived peptides in a synergistic manner.¹⁴⁹ The structures of peptides (29–31) are shown in Fig. 12.

Fig. 12 Structures of epilancin A37 (29), nukacin KSE650 (30), and lugdunin (31).

The synthesised analogue and modified thiazolidine ring were used to study the antibacterial efficacy and mode of action of lugdunin. The thiazolidine ring and modifying the D- and L-amino acid backbone were the most important factors. This process involves the dissipation of membrane potentials in specific bacterial cells. The mechanism of action revealed that this peptide's antibacterial activity maintains the integrity of artificial membrane vesicles by equalising pH gradients, hence proving proton transfer. The variety of these thiazolidine cyclopeptides is further increased by adding additional tryptophan or propargyl groups.¹⁵⁰ Its genotypic study among different strains shows that most lugdunin producing oxacillin-resistant Staphylococcus lugdunensis strains were of ST3-SCCmec V-agr II genotypes, while most lugdunin producing OSSL strains were of ST3-agr II, followed by ST1-agr I. Lugdunin exhibited weak inhibitory activity against the VISA ST239 isolate, and ST239 VSSA was more resistant to lugdunin than ST5, ST59, and ST45 VSSA.¹⁵¹ The same group conducted further research recently on the concept of lugdunin synthesis and determined that it is associated with molecular types, further strengthening their hypothesis.¹⁵² Most recently, it has been shown that lugdunin quickly destabilises the potential of bacterial membranes in vitro. The membranes of Gram-positive bacteria have lipid compositions that the peptide partitions into, however those containing cholesterol have a lower partitioning efficiency. The translocation of protons and monovalent cations is facilitated by the formation of hydrogen-bonded antiparallel β-sheets by lugdunin via peptide nanotubes upon insertion. According to the findings, lugdunin causes the bacterial cell's membrane potential to dissipate by functioning as a peptidic channel that forms spontaneously via a stacking mechanism.¹⁵³

In the case of nisins, there are many different nisin variants isolated starting back from 1928, the first one is nisin A (32), and then nisin F (33) (Fig. 13), Q (34), Z (35) (Fig. 14), from Lactococcus lactis, nisin O₁ to O₄ from Blautia obeum, nisin U (36) and U2 (37) (Fig. 15) from Streptococcus uberis, nisin P (38) from Streptococcus gallolyticus subsp. pasteurianus, nisin J (39) from Staphylococcus capitis, and nisin H (40) (Fig. 16) from Streptococcus hyointestinalis.¹⁵⁴ Nisin J is produced by Staphylococcus capitis APC 2923, a strain obtained from the microbiota of the human skin. The verification of nisin J production by Staphylococcus capitis APC 2923 has been achieved through the utilization of sophisticated analytical techniques including whole-genome sequencing and mass spectrometry. In the term of biological activity, it displayed notable antimicrobial effectiveness against a range of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and Cutibacterium acnes.¹⁵⁵ Nisin H was not isolated from human microbiota (isolated from pig);¹⁵⁶ however, nisin P was isolated from human fecal isolate, Streptococcus agalactiae DPC7040, which exhibits antimicrobial activities against many gut and food isolates because of such peptides. The antimicrobial activity of nisin P, nisin A and nisin H was studied, and it was found that nisin P was less active than the other two against Lactobacillus delbrueckii subsp. bulgaricus LMG 6901 at different time points and pH values; overall, nisin A displayed higher activity than H, and then P.¹⁵⁷ Additionally, this peptide exhibited antibacterial activity against various clinical drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and penicillin-resistant Streptococcus pneumoniae.¹⁵⁸Blautia obeum A2-162, which was obtained from the human gastrointestinal tract, exhibited antibacterial properties against Clostridium perfringens, Clostridium difficile and Lactococcus lactis. This antimicrobial activity was attributed to the presence of nisin O.¹⁵⁹ Nisin and ranalexin were tested against 40 nosocomial MRSA isolates in vitro, both alone and in combination with amoxycillin, amoxycillin-clavulanate, imipenem, clarithromycin, ciprofloxacin, rifampin, and vancomycin. At doses ranging from 1 to 32 μg ml⁻¹, both peptides effectively blocked all isolates. Except for β-lactams, other agents showed synergy when combined.¹⁶⁰

Fig. 13 Structures of nisin A (32) and nisin F (33).

Fig. 14 Structures of nisin Q (34) and nisin Z (35).

Fig. 15 Structures of nisin U (36) and nisin U2 (37).

Fig. 16 Structures of nisin P (38), nisin J (39), and nisin H (40).

Streptococcus gallolyticus subsp. is the primary pathogen responsible for septicemia and infective endocarditis (IE) in older individuals and those with weakened immune systems. It is one among the few bacteria that are opportunistic and have a substantial association with colorectal cancer (CRC). One study examined the effects of cholesterol on bacteriocin activity from this species on model membranes, as well as the cytotoxic and hemolytic capabilities of bovicin HC5 (found in this species) in vitro. The reference peptide utilised was nisin. Light microscopy and the MTT assay were used to examine the vitality of three different eukaryotic cell lines that had been treated with either nisin or bovicin HC5. The haemoglobin liberation assay was used to assess the hemolytic potential. Nisin had an IC₅₀ value of 13.48 μM and bovicin HC5 had an IC₅₀ value of 65.42 μM against Vero cells. Neither bacteriocin was inhibited by cholesterol in the DOPC model. Cholesterol had no influence on the interaction of bovicin HC5 with model membranes, and the compound only exhibited cytotoxic effects at concentrations higher than the biologically active threshold. Previously, the same researchers showed that whereas bovicin HC5 and nisin have the same target on the membrane, their capacity to create pores in model membranes is significantly different.^161,162

It has been found that loading nisin Z onto cross-linked cyclodextrin nanosponges (CDNS) successfully treated melanoma cancer both in the in vitro and in vivo studies. Nisin encased in CDNSs enhanced melanoma cancer cell line cytotoxicity and apoptosis, according to the data. Nisin placed on PMDA-NSs reduced tumour volume and weight in a mouse model of melanoma cancer, inhibiting tumour growth. Complexation with PMDA-NSs amplified nisin anti-cancer properties, which include apoptosis and antioxidant activity. Furthermore, CD31 expression in tumour tissues was reduced by nano-formulated nisin. The results indicate that the anticancer impact of nisin in melanoma cancer animal models may be enhanced by integrating it into nanosponges as a safe carrier.¹⁶³ Melanoma is the most lethal form of skin cancer, hence reprogramming cellular metabolism is crucial in cancer treatment. This peptide has the ability to fight melanoma in vitro. It causes apoptosis, increases reactive oxygen species production, and negatively affects energy metabolism in melanoma cells through selective toxicity. In addition to its possible utility against melanoma-related metastasis, it reduces melanoma cell invasion and proliferation. It is possible to treat melanoma using combination therapy using recognised anti-melanoma drugs, since nisin Z puts a heavy strain on the cell energy metabolism.¹⁶⁴ Head and neck squamous cell cancer (HNSCC) may be amenable to nisin, a bacteriocin and food preservative. When compared to primary keratinocytes, it causes HNSCC cells to undergo apoptosis, cell cycle arrest, and lessen cell growth. Moreover, in vivo, nisin decreases HNSCC carcinogenesis. A proapoptotic cation transport regulator known as CHAC1 and a calcium influx mediates this action. The work details the novel function of CHAC1 in nisin-induced cancer cell apoptosis. The results lend credence to nisin potential as a new treatment for HNSCC, and the fact that it is both safe for humans to eat and used in food preservation could speed up its introduction to clinical trials.¹⁶⁵ Another study reported that nisin exerts potent cytotoxic effects on the breast cancer cell line MCF-7, with a higher selectivity for malignant cells relative to normal cells. Nisin and doxorubicin have synergistic antitumor effects when used together. It is possible to increase the therapeutic index and decrease adverse effects in breast cancer patients by combining doxorubicin with nisin at sub-inhibitory doses.¹⁶⁶ The anticancer potential and mechanisms of nisin ZP in non-small cell lung cancer cells (NSCLC) were examined. Apoptosis, cell cycle arrest, and inhibition of cancer cell proliferation via non-membranolytic pathways were observed as effects of nisin ZP selective toxicity on cancer cells. Additionally, it showed promise in the fight against extremely metastatic NSCLC by reducing clonal proliferation and migration of cancer cells. Both the 3D spheroid development and the cell survival of A549 cells were significantly inhibited in the study. In sum, the data point to promising anticancer activity in vitro and call for its continued exploration as a potential new treatment for non-small cell lung cancer.¹⁶⁷ The effects of nisin on HuH-7 and SNU182 cell lines, which are used to study liver cancer, have been found to be substantial growth inhibition and apoptosis. The epithelial-to-mesenchymal transition contributes to the development of drug resistance, a significant problem in liver cancer. Nisin treatment resulted in a down-regulation of TWIST1 expression relative to untreated cell lines, according to an analysis of the EMT transcription factors ZEB1, SNAI1, and TWIST1. Furthermore, nisin A molecular docking assessment in the Frizzled (FZD) protein binding region confirmed that nisin A could establish hydrogen bonds with critical residues. In addition to establishing nisin function in many cell models of liver cancer, this work also generated the first identification of a connection between FZD7 and nisin.¹⁶⁸ Synergistic single platforms against many types of cancer may be possible. For such case, researchers have created a novel nanoconstruct that target DMBA/TPA-induced skin cancer in mice. This nanoconstruct is composed of oligomeric chitosan coated silver nanoparticles that are co-loaded with nisin and 5-fluorouracil. The nanostructure was created by wet reduction method, then covering it with chitosan, conjugating it with nisin, then physically loading 5-FU onto it. According to biophysical analysis, the nanostructure exhibited zeta potential, UV-visible absorption maxima, and a particle size of 72.39 nm. Restored skin histoarchitecture, improved oxidant/antioxidant balance, and a marked decrease in tumour volume and load were all observed in in vivo experiments.¹⁶⁹ One potential substitute is the use of antimicrobial peptides in conjunction with chemotherapy medications. When tested on mice with skin cancer, 5-FU and nisin showed strong anti-cancer activity. Groups treated with nisin with 5-FU together demonstrated a reduction in tumour volume and burden in in vitro investigations. The combined group had greater apoptosis rates and histoarchitecture revealed a return to normal skin tissue. Both in vivo and in vitro experiments revealed that the combination of nisin and 5-FU was synergistic.¹⁷⁰ Using SW480, HCT116, and PBMC from colorectal cancer patients, the researchers looked at how nisin affected the expression of HERV-K env, Syncytin-1, microRNA-9-5p, 192, and 205. A notable rise in microRNA-9-5p was observed in HCT116, SW480, and PBMC, while microRNA-192-5p was shown to be upregulated in SW480 and HCT116. Nevertheless, PBMC did not show a statistically significant upregulation of microRNA-205-5p. Consequently, it was determined that nisin has the ability to alter gene expressions and impede the advancement of colorectal cancer. The progression of colorectal cancer can be slowed by including nisin in the diet.¹⁷¹ Human umbilical vein endothelial cells and human keratinocytes were used to show migration and proliferation effects in vitro as part of the investigation into nisin A wound healing capabilities. The study also looked into its re-epithelization capability using an ex vivo wound healing model for porcine. Nisin A reduced proinflammatory cytokines, which may explain why it impacted cell migration but not proliferation, according to the results. The rate of re-epithelialization in porcine skin was also enhanced. Nisin A did not aid the larvae in any manner other than the direct antibacterial strategy, and it increased Galleria mellonella survival from Staphylococcus epidermidis but had no effect on E. coli. With its ability to enhance skin cell mobility, reduce bacterial growth, and mitigate the effects of lipopolysaccharide and proinflammatory cytokines, nisin A could be a promising therapeutic for wound healing.¹⁷² Using several approaches, the effects of nisin on the viability of colon cancer cells and gene expression were assessed. The results demonstrated that the apoptotic index (measured in both mRNA and protein levels) was elevated, and cell viability was markedly decreased at different nisin concentrations. The dose-dependent apoptotic effects imply that nisin has the potential to trigger apoptosis through intrinsic mechanisms, resulting in the demise of malignant cells.¹⁷³ Based on these evidences, nisin can be proved as a potential anticancer agent.

In order to provide insights for the advancement of anti-infective therapies, Liu et al. undertook a comprehensive investigation involving 3000 human skin isolates, with the objective of evaluating bacterial interactions within the human skin microbiota. The findings of their study demonstrated that the Staphylococcus hominis strain showed strong and diverse efficacy against Gram-positive infections, predominantly through the action of the bacteriocin micrococcin P1 (41).¹⁷⁴ The total synthetic form of micrococcin P1 exhibited antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, Bacillus subtilis, and Streptococcus pyogenes.¹⁷⁵ Most of the applications of this peptide have been highlighted in a previous review in more detail.^176,177

There are some other genera in human microbiota that also contribute to the profile of metabolites. For instance, Streptococcus mutans UA159, an oral pathogen, has been seen to generate mutanobactins and mutanamide (42), which demonstrate inhibitory properties against the formation of hyphae in Candida albicans. This particular interaction can be considered a subsequent consequence of the mutanobactin manufacturing process. It is worth mentioning that mutanamide, which is a derivative of mutanobactins, plays a significant role in observed inhibition. Furthermore, the fully evolved mutanobactins exhibit additional immunomodulatory characteristics.^178,179 Mutanobactin is also capable of inhibiting the growth of Gram-positive bacteria, including Enterococcus faecalis. The cell membrane of Enterococcus faecalis is disrupted by this antibiotic medication, which is also effective against other species of Enterococcus, including Staphylococcus aureus. The enzyme gelatinase, which is a metalloprotease that is secreted, is responsible for facilitating the resistance of Enterococcus faecalis organisms.¹⁸⁰ The different mutanobactins include mutanobactins A, B, C and D, which are derived from Streptococcus mutans.^179,181 Moreover, mutanobactins possess various other functions, including resistance to oxidative damage. It has been discovered that both wild-type and deletion mutants exhibit a significant reduction in growth rate when exposed to H₂O₂. Furthermore, they affirm a correlation between mutanobactin-mediated ROS resistance and biofilm development. Nevertheless, the biological significance of mutanobactin-mediated ROS tolerance in situ warrants additional investigation.¹⁸² Mutanobactins also have immunomodulatory activities, and in RAW264.7 macrophages activated with LPS, it upregulates the pro-inflammatory cytokines IL-6 and IL-12 and a downregulation of MCP-1, G-CSF, and TNF-α.¹⁸³

4.1.1.4 Bioactive peptides from Streptococcus and Fusobacterium and their biological roles. Streptococcus mutans plays a crucial role in the formation of tooth decay due to its ability to form biofilms and thrive under acidic conditions. It has the ability to produce tetramic acids, mutanocyclin and reutericyclins A, B, and C through synthesis. Reutericylin A was discovered to have antibacterial properties in these molecules, while mutanocyclin exhibits anti-inflammatory benefits. Additionally, the study found that reutericyclin A effectively inhibited the development of biofilms and the production of acid even at very low concentrations. Similarly, mutanocyclin reduced the occurrence of cariogenic Limosilactobacillus fermentum.¹⁸⁴ However, here it is to be noted that these are not actual peptides, which have smaller structures. The structures of peptides (41–42) are displayed in Fig. 17.

Fig. 17 Structures of micrococcin P1 (41) and mutanamide (42).

Mutacin 1140 (43) and mutacin-BNY266 (44) (Fig. 18), lantibiotics produced from Streptococcus mutans, displayed a broad spectrum of antibacterial activities.^185,186 Mutacin 1140 has a thioether cage structure. Their mode of action is somewhat related to nisin. It is a potent antibacterial peptide, which specifically targets lipid II, hence impeding the formation of bacterial cell walls and ultimately resulting in cell lysis. The development of mutacin 1140 lipid II complexes indicates that these complexes can create membrane pores that allow water to pass through. A single chain of mutacin 1140 is bound to lipid II and facilitates the movement of water molecules across the membrane using a single-file water transport mechanism, thus it represents a unique method of action that enhances its antibacterial capabilities.¹⁸⁷ A saturation mutagenesis library of 418 single-amino-acid variants of mutacin 1140, produced by Streptococcus mutans, was used to select compounds for the treatment of CDAD. OG253 (mutacin 1140, Phe1Ile) was identified as the lead compound in the safety screen 44TM in vitro pharmacological profiling assay, which indicated that these compounds had relatively low overall toxicity. In a hamster infection model, OG253 was discovered to possess superior in vivo efficacy and an evident absence of relapse.¹⁸⁸ The extract of Streptococcus mutans JH1140 was evaluated against six bacterial species. The results indicated that the mutacin 1140 extract exhibited significantly greater inhibitory and bactericidal activities against non-mutans streptococci than mutans streptococci. Streptococcus sobrinus was discovered to be more susceptible to the extract antimicrobial action. The eradication time for microbes that were more sensitive and less sensitive was 30 minutes and 60 minutes, respectively.¹⁸⁹ For mutacin 1140 belonging to the epidermin family, it was studied that the pharmacokinetics of mutacin 1140 was affected by charged and dehydrated residues. Dehydrated residues enhance stability, but alanine substitutions enhance the characteristics. Analogues K2A and R13A have reduced clearances and enhanced bioactivities against pathogenic microorganisms. In a model of MRSA infection, these compounds provide 100% protection at 10 mg kg⁻¹ to all infected mice, resulting in a reduction of bacterial load.¹⁹⁰ In the further study, a combination of Mu1140 K2A and R13A analogues is more efficient in treating MRSA bacteria compared to native Mu1140 or vancomycin. Additionally, these analogues demonstrated significant efficacy in the treatment of MRSA skin infections. The study indicates that these analogues have the potential to serve as future alternatives for the treatment of severe Gram-positive bacterial infections. The analogues exhibit prolonged drug elimination rates, resulting in elevated plasma concentrations over a period of time. The results endorse the ongoing development of therapeutic products utilising these analogues, indicating that they have the potential to enhance the outcome of severe bacterial infections.¹⁹¹ A study utilising the suicide vector pVA891 sought to alter the core peptide of mutacin 1140. The results revealed that out of the 14 mutants, five exhibited enhanced antibacterial activity against Micrococcus luteus ATCC 10240. The study additionally discovered that three Mutacin 1140 variants exhibited the most substantial enhancements in bioactivity against Streptococcus mutans, Streptococcus pneumoniae, Staphylococcus aureus, Clostridium difficile UK1, and Micrococcus luteus ATCC 10240, and this provides evidence that the antibacterial action might be greatly enhanced.¹⁹² Furthermore, an expression library of 418 variations was developed by conducting a study that utilised saturation mutagenesis to replace each amino acid of a lantibiotic mutacin 1140. The results indicated that the optimal activity was not dependent on all residues participating in the production of lanthionine bridges. Abu8 and Ala11 exhibited permissive substitutions, but the unsaturated bond originating from Dha5 was determined to be crucial for achieving optimal activity.¹⁹³ Mutacin B-NY266 is also a highly efficient lantibiotic that has the ability to destroy a diverse range of oral streptococci.¹⁹⁴

Fig. 18 Structures of mutacin 1140 (43) and mutacin-BNY266 (44).

Streptococcus salivarius is primarily located in the oral cavity, although it has also been discovered in the gastrointestinal tract. Furthermore, a particular strain of Streptococcus salivarius obtained from the faeces of a healthy child generates salivaricin D (45), indicating its presence in the gut microbiota. The producer strain also has a significant presence in the faecal microbiota, implying its potential for competitiveness and dominance in the gut flora. Salivaricin D is a lantibiotic that is naturally resistant to trypsin and shares similarities with nisin-like lantibiotics. This bacteriocin has a wide range of activities at nanomolar levels against several types of Gram-positive bacteria including Bacillus subtilis, Clostridium bifermentans, Clostridium butyricum, Streptococcus pneumoniae, Streptococcus suis, and many others.¹⁹⁵ The structures of peptides (45, 46 and 48) are shown in Fig. 19.

Fig. 19 Structures of salivaricin D (45), salivaricin A (46), and salivaricin 9 (48).

Another lantibiotic was isolated from Streptococcus salivarius 20P3 known as salivaricin A (46), and strains Streptococcus salivarius K12 and Streptococcus salivarius 5M6c also result in salivaricin B (47) (Fig. 20) and salivaricin D respectively. Streptococcus salivarius NU10 produced salivaricin 9 (48) which exhibited both bactericidal and bacteriolytic effects on sensitive bacterial cells while causing an increase in cytoplasmic membrane permeability. The sensitive strains exhibited pore forming activity when treated with salivaricin 9.^196–198 Barbour et al. conducted a study on the bactericidal mode of action of salivaricin B against sensitive Gram-positive bacteria. Salivaricin B was discovered to require micro-molar quantities of lantibiotics, in contrast to the very powerful nano-molar lantibiotic nisin A. It disrupted the cell wall synthesis process, leading to the buildup of the ultimate soluble cell wall precursor known as UDP-MurNAc-pentapeptide. Transmission electron microscopy revealed a decrease in the thickness of the cell wall and indications of abnormal septum formation in cells exposed to salivaricin B, without any observable alterations to the integrity of the cytoplasmic membrane.¹⁹⁹ The Streptococcus strain FF22 also produced nisin-like antibiotic streptococcin A-FF22 (49)²⁰⁰ (Fig. 21). Moreover, salivaricin G32 has been isolated from Streptococcus pyogenes, which is a nisin-like lantibiotic, and is different from antibiotic streptococcin A-FF22 in the absence of lysine in position 2, and it shows inhibitory effects against the Streptococcus pyogenes infection.²⁰¹ A human vaginal isolate, Lactobacillus salivarius CRL, produces bacteriocin from the similar class known as Salivaricin CRL 1328, which is a heat-stable peptide. This peptide has the potential to prevent urogenital infections.²⁰²

Fig. 20 Structure of salivaricin B (47).

Fig. 21 Structures of streptococcin A-FF22 (49), GllA1 (50) and GllA2 (51).

Fusobacterium nucleatum, a recently identified bacterial pathogen in humans, is linked to gastrointestinal disorders such as colorectal cancer. A screening of faecal samples produces bacteriocins (salivaricin A5 and salivaricin B) with antibacterial effects against Fusobacterium nucleatum. In vitro, Streptococcus salivarius DPC6993 exhibited a limited range of antibacterial activity specifically targeting Fusobacterium nucleatum. Within a colon fermentation model, samples that were inoculated with Streptococcus salivarius DPC6993 along with Fusobacterium nucleatum DSM15643 exhibited a noteworthy decrease in the quantities of Fusobacterium nucleatum. This suggests that treatment agents aimed at these pathogens could potentially lower the likelihood of CRC development and have a favourable effect on outcomes.²⁰³ Along with this, another bacterocin, salivaricin LHM suppressing Pseudomonas aeruginosa induced inflammation by modulating immunological response in mice. In depth, salivaricin LHM exhibits anti-Pseudomonas activity and immunomodulatory effects by enhancing the production of pro-inflammatory cytokines. It also demonstrates antibiofilm properties against target bacterium urinary tract infection in both in vivo and in vitro models.²⁰⁴

Another Streptococcus bovis HC5 strain (Streptococcus gallolyticus subsp. gallolyticus Sgg formerly known as Streptococcus bovis type I), possesses powerful antibacterial properties. It inhibits a wide range of Gram-positive bacteria and has a spectrum comparable to monensin. Although heat, proteinase K, and α-chymotrypsin were able to deactivate the crude extracts, pronase E and trypsin were unable to do so. The pore-forming peptide (Bovicin HC5), which possessed a molecular mass of about 2440 Da, is the mediator of the antibacterial action. Similar to dehydroalanines in certain lantibiotics, the peptide ended with an amino acid sequence of VGXRYASXPGXSWKYVXF.^161,205 Gallocin A is a two-peptide bacteriocin also found in Streptococcus gallolyticus subsp. gallolyticus promotes colonisation in mice. The research shows that the two peptides that make up gallocin A, GllA1 (50) and GllA2 (51) (Fig. 21), are inactive when taken individually but can kill target bacteria when combined. To provide immunity to gallocin A, the third gene in the operon, gip, is both required and sufficient. The mature peptides of GllA1 and GllA2, according to structural modelling, generate alpha-helical hairpins that are held in place by disulfide bridges that are located within the molecules themselves. The experiments validated the disulfide bond's presence in GllA1 and GllA2. There may be a new subclass of class IIb bacteriocins since the research found additional ones with comparable structures.²⁰⁶ Gallocin D, a two-component bacteriocin with strong action against vancomycin-resistant enterococci, is produced by Streptococcus gallolyticus LL009. The structural genes exhibit great variability and have seen gene shuffling with other streptococcal species, despite their strong gene synteny. In lab tests, gallocin D was examined and demonstrated action against the vancomycin-resistant Enterococcus strain EC300, with a MIC of 1.56 μM. These bacteriocins may aid in the colonisation process of Streptococcus gallolyticus, which has been linked to colorectal cancer.²⁰⁷Table 1 presents the important peptides isolated from Firmicutes along with their source and antimicrobial properties.

Table 1 Important antimicrobial peptides derived from human microbiota Firmicutes

No.	Peptide	Source	Active against	Ref.
1	Trn-α and Trn-β	Bacillus thuringiensis DPC 6431	Clostridioides difficile	42
2	Amicoumacin A	Bacillus subtilis 3	Helicobacter pylori	208 and 209
3	Gassericin A	Lactobacillus gasseri LA39	Many species, Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus	57
4	Gassericin T	Lactobacillus gasseri SBT 2055	Many Bacillus sp. Staphylococcus sp. lactic acid bacteria	53
5	Acidocin B	Lactobacillus acidophilus M46	Listeria monocytogenes, Clostridium sporogenes, Brochothrix thermosphacta, Lactobacillus fermentum, and Lactobacillus delbrueckii subsp. Bulgaricus	61
6	Acidocin J1132	Lactobacillus acidophilus JCM1132	Lactobacillus sp.	66
7	Amylovorin L471 (Lactobin-A)	Lactobacillus amylovorus DCE 471	Pseudomonas aeruginosa	71
8	Plantaricin C	Lactobacillus plantarum LL441	Lactobacillus sake, Enterococcus faecalis, Bacillus subtilis	210
9	Plantaricin EF and JK	Lactobacillus plantarum C11	Escherichia coli K-12	211
10	ABP-118	Lactobacillus salivarius subsp. salivarius UCC118	Listeria sp, Staphylococcus sp., Enterococcus sp, Bacillus sp.	212
11	Lactacin F	Lactobacillus johnsonii	Lactobacillus delbrueckii, Lactobacillus helveticus, and Enterococcus faecalis	65 and 88
12	Rhamnosin A	Lactobacillus rhamnosus 68	Micrococcus lysodeikticus	67
13	Boticin B	Clostridium botulinum 213B	Clostridium botulinum	98
14	Closticin 574	Clostridium tyrobutyricum ADRIAT 932	Clostridium tyrobutyricum B570	100
15	Bacteriocin 43	Enterococcus faecium	Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae, Enterococcus durans, Listeria monocytogenes	105
16	Bacteriocin 31	Enterococcus faecalis	Enterococcus hirae 9790, Enterococcus faecium, Listeria monocytogenes	107
17	Bacteriocin 32	Enterococcus faecalis	Enterococcus faecium, Enterococcus hirae, Enterococcus durans	106
18	Bacteriocin RC714	Enterococcus faecalis	Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes	106
19	AS-48	Streptococcus faecalis S-48	Escherichia coli, Salmonella spp., Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, Paenibacillus spp.	213
20	Ruminococcin C	Ruminococcus gnavus	Clostridium perfringens	119
21	Ruminococcin A	Ruminococcus gnavus	Clostridium perfringens	123
22	Epilancin 15X	Staphylococcus epidermidis	Staphylococcus carnosus, Bacillus subtilis, Staphylococcus simulans	133 and 134
23	Nisin A	Lactococcus lactis	Lactobacillus delbrueckii subsp. bulgaricus LMG 690, 1 methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and penicillin-resistant Streptococcus pneumoniae	157 and 158
24	Nisin J	Staphylococcus capitis APC 2923	Staphylococcus aureus, Cutibacterium acnes	155
25	Nisin P	Streptococcus gallolyticus subsp. Pasteurianus, Streptococcus agalactiae DPC7040	Lactobacillus delbrueckii subsp.bulgaricus LMG 6901	154 and 157
26	Nukacin IVK45	Staphylococcus epidermidis IVK45	Many nasal members of the Actinobacteria, Proteobacteria, and Firmicutes	147
27	Lugdunin	Staphylococcus lugdunensis	Staphylococcus aureus	148 and 149
28	Mutacin 1140	Streptococcus mutans 1140	Clostridium difficile, Micrococcus luteus ATCC 10240, Streptococcus pneumoniae, Staphylococcus aureus, Clostridium difficile UK1	188 and 192
29	Mutacin-BNY266	Streptococcus mutans NY266	Many oral streptococci	194
30	Salivaricin A	Streptococcus salivarius 20P3	All strains of Streptococcus pyogenes	214
31	Salivaricin B	Streptococcus salivarius K12	Fusobacterium nucleatum, Corynebacterium spp. GH17, Lactococcus lactis subsp. cremoris HP, Lactococcus lactis ATCC11454, Micrococcus luteus ATCC10240, Staphylococcus aureus RF122, many Streptococcus	199 and 203
32	Salivaricin D	Streptococcus salivarius 5M6c	Bacillus subtilis, Clostridium bifermentans, Clostridium butyricum, Streptococcus pneumoniae, Streptococcus suis	195
33	Salivaricin 9	Streptococcus salivarius NU10	Streptococcus pyogenes	215
34	Gallocin D	Streptococcus gallolyticus LL009	Vancomycin-resistant Enterococcus EC300	207

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4.2 In-depth analysis of Proteobacteria-derived peptides

Proteobacteria, also called pseudomonadota, is one of the major phyla of bacteria. This phylum contains one of the most studied and well-known genus of bacteria, Escherichia. Proteobacteria exhibit a vast distribution across multiple anatomical regions of the human body, encompassing the skin, oral cavity, tongue, vaginal canal, and gastrointestinal systems, in addition to their frequent presence in stool samples.^216,217 Proteobacteria are found in the gut microbiota; however, they are generally less abundant than other phyla like Firmicutes and Bacteroidetes. Numerous health disorders have been linked to changes in the relative abundance of Proteobacteria. Proteobacteria comprises several genera, including Escherichia, Helicobacter, and Campylobacter, which consist of both commensal and pathogenic species. E. coli is a prevalent resident of the human gut microbiota and can play advantageous roles such as synthesizing vital vitamins. Nevertheless, specific strains of E. coli present pathogenicity and have the potential to induce gastrointestinal illnesses. Helicobacter pylori, a bacterium belonging to the Helicobacter genus, is known to inhabit the gastric region of a significant section of the human populace. Helicobacter pylori infection has been linked to the occurrence of stomach ulcers and gastric cancer in certain individuals. However, it has also been observed to potentially have protective effects against specific esophageal illnesses and asthma.^217–219

4.2.1 Escherichia derived microcins and other peptides and their biological roles. As a Gram-negative, facultative anaerobic bacterium, E. coli has been the subject of much research and is present normally in the lower intestines of warm-blooded animals, including humans. Although a significant number of E. coli strains are benign and can even have positive effects on human health, certain strains have the potential to induce a spectrum of disorders, ranging from minor gastrointestinal infections to serious diseases.^220,221 Various strains of E. coli have yielded diverse metabolites. Microcins are a class of bacteriocins that are characteristic of their small size and consist of a limited number of amino acids. As of now, various types of microcins have been extracted from E. coli. Microcin L (52) is isolated from E. coli LR05, which displayed antibacterial activity against Shigella sonnei, E. coli, and Pseudomonas aeruginosa.²²² The study examines the mechanism by which microcin L, expressed by the gene in E. coli LR05, acts in live bacteria. It does not cause the outer membrane to become permeable and relies on the outer membrane receptor Cir. The bactericidal activity relies on the tonB protein, which facilitates the transportation of iron–siderophore complexes over the outer membrane. Microcin L bactericidal effect on E. coli relies on the proton-motive force.²²³ Microcin M (53) and H47 (54), are isolated from E. coli Nissle 1917, the microcin M showed antibacterial activities against E. coli and Salmonella, while microcin H47 exhibited antibacterial activity against Enterobacter, Shigella, Klebsiella, and Proteus spp.^224,225 An assessment was conducted to determine the antibacterial properties of E. coli Nissle 1917 against pathogenic enterobacteria. Three mutants of E. coli Nissle 1917 (ΔmcmA, ΔmchB, and ΔmcmAΔmchB) were created and compared to the original wild-type strain of E. coli Nissle 1917. The upregulated mcmA E. coli Nissle 1917 exhibited enhanced antibacterial efficacy against Salmonella. The E. coli Nissle 1917 mcmA strain effectively decreased the capacity of salmonella to adhere to and invade intestinal epithelial cells, resulting in a 56.31% reduction in invasion ability and a 50.14% reduction in adhesion ability. The culture supernatant of E. coli Nissle 1917 mcmA reduced the expression and release of IL-1β, TNF-α, and IL-6 mRNA in macrophages. E. coli Nissle 1917 mcmA has the potential to be used as genetically modified probiotics to combat the colonisation of pathogenic enterobacteria in the gastrointestinal tract.²²⁶ Enterobacteriaceae spp., which are resistant to drugs, especially Salmonella spp., are major contributors to illness and death on a global scale. A study was conducted to produce a genetically modified prototype probiotic that can effectively suppress the growth of Salmonella spp. when exposed to tetrathionate, a compound produced in the inflamed gut during salmonella infection. A plasmid-based system was created to identify and utilise tetrathionate while simultaneously generating microcin H47, which then translocated to E. coli and exhibited the capacity to impede the proliferation of salmonella in oxygen-deprived environments in the presence of tetrathionate, resulting in a competitive fitness when exposed to 1 mM tetrathionate. Thus, this study showcases the feasibility of manipulating a strain of E. coli to utilise an environmental cue for the purpose of synthesising a microcin.²²⁷ One of the investigations indicate that receptor outer membrane proteins responsible for binding ferric catechol siderophores play a vital role in the particular attachment of microcin to the cell surface. Additionally, the TonB pathway is necessary for the uptake of microcin H47 and the existence of the ATP synthase complex.²²⁸ Genetic analysis was performed on microcin-resistant atp mutants to determine whether mutations affected the Fo subunit of ATP synthase. Recombinant plasmids were made with different parts of the atp operon and put them into a strain that had the atp gene deleted. Phenotypic research demonstrated that microcin H47 activity needed the Fo proton channel but did not require the F1 catalytic domain. Antibiotic resistance would set in even if one of the three parts of the proton channel were absent.²²⁹ The overexpression of the antimicrobial peptide microcin H47 in probiotics has been associated with inhibitory action against enteric pathogens in vivo, suggesting that specific strains of E. coli may generate it. The ability of microcin H47 to suppress Salmonella strains has been the subject of mixed findings. Researchers have isolated and overexpressed a variant of microcin H47 called microcin H47 monoglycosylated enterobactin. They then utilised this variant to determine the minimal inhibitory concentrations (MICs) against different Enterobacteriaceae, such as Salmonella and MDR strains. According to the findings, microcin H47 has a wide range of effects on Enterobacteriaceae, which makes it a promising drug for the treatment of multidrug-resistant infections in the intestines.²³⁰ Recently, the competitive advantage of E. coli, which coexists with mice, was examined in comparison to Salmonella enterica serovar Typhimurium (S. Tm). The work utilised a mouse model of salmonellosis to demonstrate that inflammation induces the production of the antibiotic microcin H47 toxin, which can modify the proliferation of S. Tm. Nevertheless, the ability of the E. coli 8178 tonB-dependent catecholate siderophore uptake mechanism to defend against harm is weakened when it is disrupted, revealing an unexpected connection between iron absorption and the activity of microcin H47. It displays the defensive role of gut microbiota and impact of microcins in bacterial antagonistic interactions.²³¹ The structures of (52–54) are displayed in Fig. 22.

Fig. 22 Structures of microcin L (52), microcin M (53), and microcin H47 (54).

Different colicins are produced by and also toxic for some strains of E. coli, including microcin V (previously colicin V).²³² Different types of comparison were used to examine strains that produce microcin V, colicin E3, and colicin E7. Although microcin V was determined to be the least potent toxin in paired interactions, it consistently outperformed colicin E3 in competitions involving these strains.²³³ A lasso peptide, which has a lasso knot structure, has also been isolated with the name microcin J25 (55) (Fig. 23) from E. coli AY25 isolated from human feces and it is active against E. coli, Salmonella spp. and Shigella flexneri.²³⁴ To pass through the cell membrane, the majority of microcins and colicins that rely on TonB use siderophore receptors. Only microcin 24 (also known as microcin N) relies on FhuA, the receptor for the hydroxamate siderophore ferrichrome. In E. coli, microcin J25 is also uptaken by FhuA. However, microcin 24 is sensitive to Salmonella enterica serovar Typhimurium, whereas microcin J25 is resistant to it. Proving that microcin 24 recognises a wider range of hosts than microcin J25.²²⁴ Thirty years of research on microcin J25 has been reviewed recently by Baquero et al.²³⁵ A IId peptide with unmodified, linear, non-pediocin-like, single-peptide bacteriocins was isolated from E. coli G3/10 and is known as microcin S, which also exhibited antibacterial activities.²³⁶

Fig. 23 Structures of microcin J25 (55), microcin C7 (56), microcin C51 (57), and microcin C (58).

Microcins C7/C51 (56, 57), B, and C (58) (Fig. 23) are also reported to be isolated from E. coli with antibacterial properties.^28,237 An amide bond connects the carbonyl of the C-terminal aspartic acid residue to a modified nucleotide unit, which forms the main chain of microcin C7. In vitro, protein translation is inhibited by microcin C7 and the peptide, while a synthetic n-aminopropanol substituent has no effect. Microcin C7 antibiotic action is due to the peptide, and transport requires the C-terminal substituent.²³⁸ The mechanism involves the mature microcin C7 passing through the pore protein OmpF on the outer membrane of the bacterial cell and subsequently through the inner membrane of the bacterial cell, once the translation changes are finished. The YejABEF ABC transporter specifically identifies f-Met at the N-terminus of the microcin C7 peptide and facilitates the transport of microcin C7 into cells. Once this peptide enters a target bacterial cell, the process of microcin C7 processing commences. The complete mechanism and structural description have been reviewed recently by Yang et al.²³⁹

4.2.2 Pseudomonas-, Klebsiella-, and Enterobacter-derived peptides with their biological actions. Pseudomonas species can inhabit various niches within the human body and are documented as opportunistic pathogens competent of causing a range of infections. One of the well-known examples is Pseudomonas aeruginosa, which exhibits exceptional metabolic adaptability, allowing it to flourish in a wide range of environmental circumstances. It produces a plethora of extracellular toxins, including phytotoxic factors, pigments, hydrocyanic acid, proteolytic enzymes, phospholipases, enterotoxins, exotoxins, and slime. The development of protein exotoxins is a crucial element that contributes significantly to the pathogenicity of Pseudomonas aeruginosa. This particular pathogen exhibits opportunistic behaviors and has been associated with a range of clinical manifestations, such as pneumonia, urinary tract infections, and sepsis. It is particularly prevalent in individuals with impaired immune systems, including neutropenic cancer patients, burn victims, and individuals with AIDS.^240–243 Few metabolites have been reported from such genera, for example, pyoverdine (pyoverdin) (59), a siderophore synthesized by Pseudomonas aeruginosa, plays a crucial role in the development of mammalian infections.²⁴⁴ A study has suggested using nanomaterial-based methods to regulate the characteristics of biofilms and pathogenicity. Pyoverdine was employed as a biological corona for the synthesis of silver nanoparticles (AgNPs) with the purpose of specifically targeting microbial infections. Pyoverdine-AgNPs efficiently suppressed and eliminated both the early stage and fully developed biofilms of these pathogens. The addition of pyoverdine-AgNPs enhanced the vulnerability of developed mature biofilms of Staphylococcus aureus and Candida albicans to tetracycline, pyoverdine, and amphotericin B. In addition, PVD-AgNPs reduced certain virulence features in Pseudomonas aeruginosa, including the suppression of protease activity, motility, and the generation of pyoverdine and pyocyanin.²⁴⁵ Researchers at BabylIt hospitals took blood samples from 150 patients who had burns or wounds. In order to increase pyoverdine synthesis, Pseudomonas aeruginosa was grown in a Luria–Bertani medium. There were fifty different isolates found in the patients, with 70% of the cases involving burns and 30% involving wound infections. Out of the fifty isolates tested, only four yielded pyoverdine. Most of the Pseudomonas aeruginosa strains were found to be multidrug-resistant when tested against 17 commonly used medications. Using the Congo red technique, 8 out of 50 isolates were shown to have the potential to form biofilms. More fruitful were Ps1 and ps4, and pyoverdine also showed anticancer action against skin cancer cells and lung cancer cells.²⁴⁶ Urinary tract infections developed as a result of using a catheter are a prevalent type of healthcare-associated infection, caused by the introduction of bacteria into the bladder. The generation of pyoverdine was evaluated in many isolates of Pseudomonas spp., with Pseudomonas aeruginosa exhibiting the highest pyoverdine production. The purified pyoverdine effectively suppressed biofilm development, showing inhibition rates of 62–85% after 24 hours and further increasing to 69–89% after 48 hours. The E. coli isolates exhibited the greatest degree of inhibition, with a percentage of 100%. Enterococcus faecalis showed a little lower inhibition rate of 77%, while Proteus mirabilis displayed a lesser inhibition rate of 62%.²⁴⁷ Different types of pyocins (bacteriocin) were isolated from Pseudomonas aeruginosa which are type S and type R.²⁴⁸ Pyocin S2, synthesised by Pseudomonas aeruginosa M47, suppressed the proliferation of diverse mammalian cells, encompassing both tumour and non-cancerous cells. The inhibitory effects were enhanced by the action of pyocin S2. Nevertheless, certain tumour and normal cells exhibited resistance to pyocin 2. Cell membrane preparations derived from pyocin S2-sensitive cells effectively neutralised the action of pyocin S2, whilst preparations from pyocin-resistant cells did not. The neutralisation capacity was hindered by high amounts of D-galactose, N-acetyl-D-galactosamine, and N-acetyl neuraminic acid, while it was entirely destroyed by periodate and neuraminidase. The inhibitory effect of saccharides varied with their concentration. The cytotoxicity of pyocin S2 towards mammalian cells may be attributed to its specific interaction with the cell membrane.²⁴⁹ Increased pyocin production of 65.74 percent was seen after using mitomycin C, an inducer of pyocin secretion. Even Gram-positive and Gram-negative bacteria were unable to grow in the presence of these S-type pyocins. The fact that S-type pyocin was shown to be resistant to both physical and chemical factors indicates that it could be used as a treatment for infections and harmful bacteria. Given that it can withstand changes in temperature, pH, and organic solvents, it can find use in many different domains including pharmaceutical sectors.²⁵⁰ In bacterial rivalry, big proteomic structures called phage tail-like bacteriocins (PTLBs) help one side by penetrating the other membranes. The tail fibre and lipopolysaccharide type govern the specific range of action for each type. Genome sequences from 32 clinical Pseudomonas aeruginosa isolates were used to identify R-type and F-type pyocins. These pyocins were then grouped into four categories according to the homology, phylogeny, and structure of the cluster components and tail fibre. A wide range of activity, from 0% to 37.5%, was seen in the biologically active spectrum of typical pyocins.²⁵¹ One third of the 52 Pseudomonas strains tested in a study of Nigerian patients suffering from burns, wounds, skin, UTI, diarrhoea, and eye infections were found to produce pyocins at concentrations ranging from 410 to 670 g ml⁻¹. The yields of pyocins were highest between 35 and 37 °C, and they dropped dramatically beyond 37 °C. The growth of the Pseudomonas putida indicator strain was inhibited by pyocins produced by 25 different strains; of these, 4 strains had inhibition zones with diameters greater than 3 mm. Some Gram-positive and Gram-negative bacteria isolated in such study, such as Bacillus cereus, Listeria monocytogenes, Klebsiella spp., Staphylococcus aureus, Staphylococcus epidermidis, Proteus spp., and Vibrio parahaemolyticus, showed growth inhibitory activity when exposed to these pyocins.²⁵²Klebsiella commonly causes nosocomial infections in humans. One of the well-known species is Klebsiella pneumoniae, which is a widely recognized species that presents a substantial risk as a primary contributor to sepsis arising from pneumonia in the human population, frequently leading to increased rates of illness and death. The microbiota is essential for enhancing and controlling the host immune response during bacterial infections. Nevertheless, Klebsiella pneumoniae poses significant difficulties as a highly resistant organism that is resistant to multiple drugs, hence worsening the severity of infections. This increased resistance exacerbates the current limitations in treatment choices, hence further contributing to the elevated rates of illness and death associated with Klebsiella pneumoniae infections.^253–256Klebsiella pneumoniae also produces microcins as like E. coli. Microcin E492m is a post-translationally modified version of the antibacterial peptide microcin E492 of Klebsiella pneumoniae. This alteration, which imitates a siderophore, attaches to ferric ions and is more powerful than microcin E492. The alteration improves the ability of the microcin to be recognised and its ability to kill microorganisms, making it the inaugural member of a novel category of siderophore-peptides. Microcin 492m has more potency compared to microcin E492, and its wider range of antibacterial action renders it a highly attractive option for further investigation.²⁵⁷Klebsiella pneumoniae releases siderophores, which are tiny molecules that form chelates with iron. These siderophores facilitate the acquisition of iron from the host, hence facilitating the progression of infection. The role of siderophores as secondary metabolites involves the facilitation of iron sequestration from the surrounding environment and its subsequent transfer into the intracellular compartment of bacterial cells. Siderophores secreted during infection can impact the location of tissues, the spread of the infection throughout the body, and the host's ability to withstand the infection.²⁵⁸ Colibactin (60) is a bacterial toxin, and it appears for the occurrence of colorectal cancer, is produced by Klebsiella pneumoniae²⁵⁹ (it also found in E. coli).²⁶⁰ The mechanism of action, biosynthesis, structural description and related description of this toxin has been carefully evaluated in many review articles.^261–268

The genus Enterobacter, part of the Enterobacteriaceae family, is predominantly associated with infections in healthcare settings. Enterobacter species are primarily associated with nosocomial infections, although they can also infrequently cause community-acquired diseases including urinary tract infections, pulmonary infections, soft tissue infections, osteomyelitis, and endocarditis, among other ailments. Nevertheless, it is crucial to acknowledge that not all are implicated in human suffering.²⁶⁹ This genus possess a specific gene for the synthesis of endotoxin and uraemic toxins such as 4-hydroxy phenyl lactate, p-cresol sulfate, indoxyl sulfate, indole-3 acetic acid, trimethylamine-N-oxide, and imidazole propionate.²⁷⁰ As mentioned earlier, Colibactin, a bacterial toxin, was also found in the clusters of Enterobacter aerogenes. However, as a whole this is very less studied in case of metabolites.¹¹⁴ There are many other bacteria from phylum Proteobacteria that are a part of human microbiota. However, their contribution to the metabolite profile is quite low. Some of them have made little contribution other than discussed before. The ability to create virulence factors and withstand high temperatures is an evolutionary hallmark of human infections. Recently, it has been found that blood of a sick child yielded the pathoadapted bacterium Luteibacter anthropi. Genome comparisons showed that compared to other bacteria, Luteibacter anthropi possesses a distinct NRPS gene locus that codes for metallophore production, and it also has a greater metabolic capacity. A new family of nonribosomal peptides called anthrochelins A–D (61–64) were discovered, and they are derived from salicylates. A homocysteine tag, likely added during peptide termination, is located at the C-terminus of these peptides.²⁷¹

Other genera in human microbiota from Proteobacteria include Helicobacter, Campylobacter, and Vibrio. They are mostly acting as pathogens to humans. For instance, the relationship between Helicobacter pylori infection and changes in the gut microbiota has been the subject of multiple studies. A considerable body of research has been dedicated to investigating the impact of eradication therapy on the gut flora. The prevalence of Helicobacter pylori infection exceeds 50% among the worldwide population. Vacuolating cytotoxin A is a prominent virulence factor synthesized by Helicobacter pylori, and such toxin is composed of the p33 and p55 subunits, attaches to host cells and causes significant vacuolation after being released through a type V auto transport secretion system.^272–274Campylobacter is a widespread cause of diarrheal disease worldwide. Butyric acid, a metabolite produced by microorganisms, plays a crucial role in inhibiting the colonization of Campylobacter jejuni by the gut microbiota. Furthermore, both butyric acid and deoxycholic acid play a role in mitigating colitis produced by Campylobacter jejuni.^275–277 The harmful bacterium known as Vibrio cholerae is the reason for the severe diarrheal illness known as cholera, which affects millions of people every year and is responsible for more than 100 000 deaths each year. At the beginning of the infection, Vibrio clings to epithelial cells and begins to multiply.

This is where the infection begins. Vibrio, once it has entered the human digestive system, launches a wide variety of complex pathogenic factors. An important factor that contributes to the severity of diarrheal sickness is the production of cholera toxin by Vibrio cholerae, which is one of these. The cholera toxin, which is classified as a heat-labile enterotoxin and is a member of the AB toxin family, is an essential component in the evolution of the disease called cholera.^278–280 The structures of (59–64) are shown in Fig. 24.

Fig. 24 Structures of pyoverdin (59), colibactin (60), and anthrochelins A–D (61–64).

4.3 Biological roles of Actinobacteria (Actinomycetota)-derived peptides

Actinobacteria have been detected in various sites of the human body, including mucosal surfaces and the skin. They are essential components of a healthy microbiota. Their presence and abundance in these specific sites correlate with the individual's health status. This phylum also contains those bacteria that cause tuberculosis and diphtheria. Although they make up only a small percentage of the gut microbiota, they play a key role in maintaining gut homeostasis.^281–283 They comprise numerous taxa that are highly significant, such as Bifidobacterium, Corynebacterium, Rhodococcus, and Mycobacterium, in terms of extracting peptides.

4.3.1 Bifidobacterium- and Corynebacterium-derived peptides and their biological activities. Bifidobacteria are essential components of the gut microbiota, which consist of bacteria that reside in the gastrointestinal tract of humans. These microorganisms are among the first to establish themselves in the human gastrointestinal tract and are notably prevalent in the gut microbiota of mammals, especially in the early stages of infancy. Bifidobacteria are well known for their positive effects on health and are frequently included in functional meals. Selected strains of bifidobacteria have exhibited effectiveness in the reduction and prevention of several oral and gastrointestinal inflammations, such as irritable bowel syndrome, enhancement of intestinal barrier functions, and alleviation of symptoms associated with baby colic.

Moreover, several strains have demonstrated the capacity to mitigate cutaneous inflammations, such as eczema and atopic dermatitis, in newborns. Within the human gut microbiota, Bifidobacterium is among the most prevalent genera. They make up 3–7% of the adult digestive tract population and as much as 91% of the entire population in newborns.^284–288 Yu et al. have recently studied, where they re-evaluated numerous Bifidobacterium species that were previously believed to have limited capacities to produce bacteriocins. The identification of bacteriocin genes in these species indicates that they have a distinct advantage in establishing themselves in the intestinal tract of infants. The presence of many biosynthetic gene clusters was observed in Bifidobacterium longum subsp. infantis, encompassing various groups responsible for the synthesis of lanthipeptides, lasso peptides, thiopeptides, and class IId bacteriocins. The potential for bacteriocin production was demonstrated by confirming the antibacterial potency of the crude bacteriocins by bioassays and transcriptional analysis.²⁸⁹ A lantibiotic, BLD 1648, has been reported from bifidobacterium longum DJO10A.⁶⁵Bifidobacterium longum BL-10 also possess 15 antioxidant genes, which displayed strong reducing power activity and scavenging activity of DPPH, hydroxyl radicals, and superoxide anions,²⁹⁰ which is a clue that it contains specific metabolites that have the antioxidant potential, in such case, an amino acid metabolite, phenylacetic acid, has been reported from Bifidobacterium.²⁸ The bacteriocin production of five different strains of Bifidobacterium bifidum was examined in MRS broth supplemented with 0.05% cysteine. The only bacteriocin that NCFB 1454 released was bifidocin B (65) (Fig. 25). Bifidocin B inhibited the growth of certain Gram-positive and Gram-negative bacteria, including those responsible for food poisoning and spoilage, such as Listeria, Enterococcus, Bacillus, Lactobacillus, Leuconostoc, and Pediococcus species.²⁹¹ Furthermore, it was shown that bifidocin B exhibited adsorption specifically to Gram-positive bacteria. The adsorption exhibited pH dependency but not time dependency. Bifidocin B exhibited fast adsorption and lethal activity against susceptible cells. Cellular binding of bifidocin B was not reduced by pre-treatment with detergents, organic solvents, or enzymes. The ability of cell wall preparations to absorb bifidocin B was diminished when treated with methanol : chloroform and hot 20% (w/v) TCA. Bifidocin B adsorption was inhibited by the introduction of pure heterologous lipoteichoic acid.²⁹² Bifidin, bacteriocin generated by Bifidobacterium bifidum NCDC 1452, is the first bacteriocin thought to be associated with Bifidobacterium. When it is cultured in skim milk, its antibacterial activity is at its peak, also its activity become high even after being partially cleansed and stored in the cold.²⁹³ Bifidin I, a novel bacteriocin derived from Bifidobacterium infantis BCRC 14602, was purified using a three-step purification procedure. Bifidin I exhibits potent antilisterial activity and effectively inhibits the development of both Gram-positive and Gram-negative bacteria, which are responsible for food deterioration and foodborne illnesses. Consequently, it has considerable potential for application in ensuring food safety.²⁹⁴ Bifilong from bifidobacteria also possess bacteriocin characteristics. This compound possesses heat stability, is composed of proteins, and exhibits activity within a pH range of 2–10. It can efficiently fight against various Gram-positive species, such as bifidobacteria, lactobacilli, clostridia strains, and certain streptococci strains.²⁹⁵

Fig. 25 Structure of bifidocin B (65).

4.3.2 Rhodococcus-, Mycobacterium-, and other genera-derived peptides and their biological activities. Infections caused by Rhodococcus spp. have the potential to manifest in diverse regions of the human body. Rhodococcus erythropolis is a prominent species that inhabits several parts of the body, such as the skin, mouth, and gastrointestinal tract (GIT). Rhodococcus erythropolis exhibits substantial antibacterial efficacy against a diverse array of microorganisms.

The analysis of biosynthetic gene clusters in Rhodococcus erythropolis and Rhodococcus equi revealed the existence of the requisite genetic material for the manufacture of humimycin, resulting in the generation of two distinct humimycin A (66) and B (67). In mouse models, these humimycins demonstrate the capacity to impede lipid II flippase and augment the efficacy of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus. This finding exhibits potential for the advancement of innovative therapeutic approaches.²⁹⁶ Furthermore, Rhodococcus erythropolis is capable of synthesizing siderophores, such as heterobactins A (68) and B (69), consisting of tripeptide sequence ((N-OH)-L-Orn-Gly-D-Orn- (delta-N-dihydroyxbenzoate)). Experiments on growth promotion with different transport mutants showed that the catecholate receptor Cir is the sole E. coli heterobactin A receptor, whereas a hydroxamate transport system is responsible for the uptake of heterobactin B in both E. coli and Microbacterium flavescens JG9.²⁹⁷ The structures of (66–67) and (68–69) are shown in Fig. 26 and 27, respectively.

Fig. 26 Structures of humimycin A (66) and humimycin B (67).

Fig. 27 Structures of heterobactin A (68) and heterobactin B (69).

Mycobacterium species encompasses a wide range of acid-fast, aerobic bacteria that are distinguished by their sluggish growth rate. There are more than 70 different species in this genus, and around 30 of them have been associated with diseases in humans. Mycobacterium tuberculosis is of particular importance as the major etiological agent responsible for tuberculosis.²⁹⁸ Phthiocerol dimycocerosates are a notable category of lipids that have been identified as significant factors in the pathogenicity of Mycobacterium tuberculosis. The exterior surface of virulent strains within the Mycobacterium tuberculosis complex has a notable abundance of glycolipids, which serve crucial functions in the pathogenicity of the bacterium.^299,300 Lipoarabinomannan is a glycolipid that plays a crucial role in the structural composition of the cell wall of Mycobacterium tuberculosis, the pathogen responsible for tuberculosis. Such glycolipid operates as a virulence factor through its ability to hinder the activities of monocytes and eliminate oxidative radicals. Lipoarabinomannan has been observed in the urine of specific individuals diagnosed with tuberculosis.³⁰¹ Mycolic acids have also been reported from Mycobacterium with immunomodulatory activities.²⁸

There are many other genera of Actinobacteria which reside in humans and represent metabolites profile and many other biological activities. Nocardia belongs to Actinobacteria is pathogenic bacteria to humans and it causes human infection called nocardiosis. It is also known to produce a variety of compounds with antitumor, and antimicrobial activities. Brasilinolide A (70), brasilinolide B (71) (Fig. 28), and transvalencin Z (72) have been reported from Nocardia.^302–304 Brasilinode A exhibits significant antifungal activity against Aspergillus niger, with a minimum inhibitory concentration of 3.13 μg ml⁻¹. Furthermore, it demonstrated immunosuppressive effect in the mixed lymphocyte reaction test technique.³⁰⁵ Transvalencin Z exhibits significant antibacterial activity against Gram-positive bacteria, while without any cytotoxic effects. It exhibits specific antimycobacterial effects against Mycobacterium smegmatis. Furthermore, it exhibited antimicrobial properties against fungi such as Trichophyton mentagrophytes and Cryptococcus neoformans. The antibiotic exhibits activity against Gram-positive bacteria, including Micrococcus luteus.^303,306,307 Nocardithiocin (73), a thiopeptide compound synthesised by Nocardia pseudobrasiliensis strain IFM 0757, demonstrates potent activity against Mycobacterium and Gordonia species. It effectively inhibits both rifampicin-resistant and sensitive strains of Mycobacterium tuberculosis at concentrations ranging from 0.025 to 1.56 μg ml⁻¹.³⁰⁸

Fig. 28 Structures of brasilinolide A (70), and brasilinolide B (71).

Many siderophores have been isolated from Nocardia spp. For instance, JBIR-16, brasilibactin A, asterobactin, nocobactin NA and nocardamine (74–78).³⁰⁹ JBIR-100 exhibits significant antibacterial properties. When Bacillus subtilis is treated with JBIR-100, it causes the permeabilization and depolarization of the cell membrane.³¹⁰ Treatment with ferric chloride diminished the antibacterial properties of brasilibactin A against Staphylococcus aureus and Micrococcus luteus, with MIC values of 0.73 and 4.5 mg ml⁻¹, respectively. There was a concentration-dependent increase (0.3–3 μM) in caspase-3 activity in HL60 cells, while it also showed strong cytotoxicity against murine leukaemia L1210 and human epidermoid carcinoma KB cells (IC₅₀, 0.02 and 0.04 μg ml⁻¹, respectively).³¹¹ At concentrations ranging from 0.2 to 3.2 μg ml⁻¹, asterobactin demonstrated anticancer efficacy against a number of cultured cell lines, including HL-60 and HeLa cells.³¹² The structures of (72–77) and (78) are shown in Fig. 29 and 30, respectively.

Fig. 29 Structures of transvalencin Z (72), nocardithiocin (73), JBIR-16 (74), brasilibactin A (75), asterobactin (76), and nocobactin NA (77).

Fig. 30 Structure of nocardamine (78).

Collinsella is a genus of Gram-positive anaerobic bacteria that are classified within the Actinomycetota phylum and are commonly found in the human gut microbiome. Additionally, it contributes to the development of health conditions such as rheumatoid arthritis and irritable bowel syndrome. Collinsella has the potential to impact metabolism through its ability to modify the absorption of cholesterol in the intestines, reduce glycogenesis in the liver and enhance the production of triglycerides.³¹³ In the human skin microbiota, Propionibacterium acnes is a Gram-positive bacterium that is considered a normal constituent. Additionally, it can be observed throughout the mouth cavity, large intestine, conjunctiva, and external ear canal. Propionibacterium acnes is the predominant bacterium found on the surface of the human skin, especially in the sebaceous regions. It is widely postulated that it exerts an influence on the pathogenesis of acne vulgaris, a persistent inflammatory dermatological disorder that impacts around 10% of the global populace.³¹⁴ Many more species within this phylum are likely to produce many metabolites, given their close relationship to other species in the same phylum.

4.4 In-depth analysis of Bacteroidetes-derived peptides

The Bacteroidaceae family is widely distributed in the gut microbiota and exhibits a greater ability to engage with their host and break down complex polysaccharides. Their metabolic processes frequently yield acetate, propionate, and succinate.^315,316 The metabolite profile of human microbiota is significantly influenced by most genera within the Bacteroidetes group. As previously stated, both Firmicutes and Bacteroidetes constitute most of the human gut microbiota, comprising over 90% of the total microbial population. However, the addition of peptides to metabolic profile from this phylum is not as substantial compared to Firmicutes.

The obligately anaerobic bacteria of the genus Bacteroides, which are a significant component of the Bacteroidetes phylum, have drawn considerable attention in the field of human gut microbiology since their original identification. The strong adaptation of these microbes to their specific biological niche is highlighted by their exclusive localization and proliferation within the gastrointestinal tracts of mammals. These microbes possess the ability to form long-lasting and mutually advantageous relationships with their human hosts, functioning as both commensals and mutualists. As a result, they provide a wide range of health-enhancing effects.^317–319

In the case of metabolites, Bacteroides fragilis or its cell-free supernatant was used to inhibit in vitro Salmonella Heidelberg translocation, and such friction was then analyzed by Liquid Chromatography High-Resolution Tandem Mass Spectrometry along with the Molecular networking to display the possible compounds in such activities, and cholic acid and deoxycholic acid were found to be the responsible metabolites.³²⁰ Different species, i.e., Bacteroides thetaiotaomicron, Bacteroides eggerthii, Bacteroides ovatus, Bacteroides fragilis, Parabacteroides distasonis, were tested for the metabolite production, but these are not the peptides we are searching for.³²¹

Commendamide, or N-(3-hydroxypalmitoyl)-glycine (79) (Fig. 31), is a biologically active compound that is synthesized by the gut microbiota, Bacteroides vulgatus. It exhibits a similar structure to long-chain N-acyl-amino acids, which are components of the complex lipid signalling system known as the endocannabinoidome. It plays essential roles in mammals by stimulating different receptors such as G-protein-coupled receptors.^322,323 Coyne et al. performed a comprehensive analysis of 140 distinct strains of Bacteroides and Parabacteroides found in the human stomach. Out of them, a total of 15 unique species were identified, and four of them were shown to produce a metabolite that specifically targets many species of Bacteroides and Parabacteroides. There are four strains of Bacteroides ovatus (BoCL02T12C04), Bacteroides thetaiotaomicron (BtCL15T12C11), and two strains of Bacteroides vulgatus (BvCL01T12C17 and BvCL14T03C19) that can generate toxins. Furthermore, the confirmation of the existence of bacteroidetocin A (80) and B (81) (Fig. 32) were obtained in many strains.³²⁴ As there are many species of Bacteroides present in humans, very few have been studied for metabolites so far.

Fig. 31 Structure of commendamide (79).

Fig. 32 Structures of bacteroidetocin A (80) and bacteroidetocin B (81).

4.5 Biological functions of Fusobacteria-derived peptides with their role in human disorders

The phylum Fusobacteria comprises bacteria that exhibit obligate anaerobic characteristics, possess a Gram-negative nature, and do not form spores. They are rod-shaped, cylindrical bacilli with sharp tips. This species is quite prevalent in the oral cavity, found in both individuals with diseases and healthy. Periodontal illnesses, ranging from moderate reversible gingivitis to severe irreversible periodontitis, are associated with its involvement. Fusobacteria are a constituent of the indigenous microbiota within the human body and commonly present in the gastrointestinal system and female vaginal tract. Nevertheless, these microbes have the potential to induce various infections and abscesses, such as Lemierre's syndrome, acute and chronic mastoiditis, chronic otitis and sinusitis, tonsillitis, peritonsillar and retropharyngeal abscesses, and postanginal cervical lymphadenitis.^325–327

Fusobacteria are commonly present in the oral, gastrointestinal, and vaginal microbiota, but they can cause septic thrombophlebitis in the adjacent neck arteries when the infection is linked to an oropharyngeal abscess. Several reliable studies conducted on Fusobacterium have reported an annual incidence of bacteremia at a rate of 0.55 cases per 100 000 individuals, along with a diverse range of clinical manifestations. Fusobacterium nucleatum and Fusobacterium necrophorum are the predominant species that have been isolated within this particular genus.^328,329 The immunostimulatory molecules known as muramyl dipeptide (82) and muramyl tripeptide (83) (Fig. 33) are produced from the cell walls of bacteria. These entities play a crucial role in the composition of the bacterial peptidoglycan layer, which serves as a defensive shield enveloping bacterial cells. N-Acetylmuramic acid and L-alanine are the constituent amino acids of muramyl dipeptide, whereas muramyl tripeptide include an extra amino acid, D-isoglutamine. Muramyl dipeptide and tripeptide have been reported from the Fusobacterium nucleatum, which displayed immunomodulatory activity.^28,330 Short-chain fatty acids are also released from Fusobacterium nucleatum as end-products of its metabolism. These Short-chain fatty acids act as neutrophil chemoattractants through free fatty acid receptor 2.³³¹ Another genus within the same phylum that is found in the human microbiota is Leptotrichia, which are non-motile facultative anaerobic/anaerobic microorganisms mostly distributed in the mouth cavity and certain regions of the human body.³³² There exist several additional genera within this phylum that have not been extensively investigated in relation to the isolation and purification of metabolites. A similar situation is also observed in the context of the Verrucomicrobia phylum.

Fig. 33 Structures of as muramyl dipeptide (82) and muramyl tripeptide (83).

5 Future challenges and conclusive remarks

The human gut microbiota consist of trillions of symbiotic microbial cells in every individual. Genomics has facilitated the identification of a wide range of natural chemicals using a technique to which we can say “genomic guided isolation”. The metabolic function of gut microbial species is influenced by the presence of these essential substances derived from the diet, which in turn affect the functioning of the host organism. These metabolites include various significant categories of secondary metabolites, such as lantibiotics and bacteriocins, microcins and thiazole, enterotoxin, glycolipids, terpenoids, and, polyketides and nonribosomal peptides.^{28,33,333,334}

After performing an extensive analysis of existing research, it is evident that Firmicutes, followed by Actinobacteria, and Proteobacteria are the three phyla of the human microbiota that have gained considerable interest, particularly in relation to their peptides. Nevertheless, there is a dearth of research on the investigation of metabolites in the other phyla. Although Firmicutes and Bacteroidetes make up the largest portion of the human gut microbiota, accounting for over 90% of the total microbial population, Bacteroidetes has received less attention in terms of its metabolites. In addition, there has been limited focus on studying the metabolites associated with Fusobacteria and Verrucomicrobia, resulting in a significant knowledge gap in the connection between human microbiota and metabolites. To fill this gap, it is necessary to make progress in current chromatographic, spectroscopic (including mass spectrometric), genomic, and computational techniques. Due to the persistent challenges faced by these primary techniques, such as restricted metabolite detection, current methodologies require enhancement to successfully identify numerous bioactive chemicals that may remain undetected due to their low abundance or complex chemical structures. Along with this, the dynamic nature of microbiota, which is impacted by several aspects such as health status, environment, and nutrition, necessitates further investigation, as existing methodologies are not progressively addressing this topic over time. The integration of multi-omics data presents a substantial difficulty in elucidating the microbiota characteristics and intricacies. Torres et al. have recently examined 444 054 small protein families derived from 1773 human metagenomes to assess their antibacterial capabilities. Their findings revealed the existence of many compounds in the human microbiome that may be confirmed as possible antibacterial agents using contemporary methods.³³⁵ Another key necessity to address is the improvement of preclinical and clinical trials that can effectively bridge this gap.

These enhancements are essential for further exploration into the complex realm of metabolites linked to the human microbiota, ultimately enhancing our comprehension of its functional significance in human health and disease. The pursuit of new antimicrobial drugs has become a crucial effort in addressing the significant challenges presented by antibiotic resistance. Studying the environments where harmful bacteria thrive and investigating how their ecological rivals control them have produced encouraging findings. The application of this theoretical framework to develop practical treatments for severe infections and widespread disorders can be enhanced by identifying and studying various antibacterial substances obtained from the human microbiome.

Since the advent of antibiotics in the twentieth century, several medications have become potent instruments in the treatment of a wide range of diseases and ailments. Furthermore, antibiotic resistance has emerged as a serious problem due to improper and incorrect use; if not addressed, this pandemic might wipe out millions of people. It is one of the leading causes of death worldwide in 2019, with 1.27 million fatalities attributable to AMR and 4.95 million deaths, according to the World Health Organization (WHO). Significant monetary expenditures accompany AMR, which also causes death and disability. By 2050, AMR would drive up healthcare expenditures by $1 trillion and reduce GDP by $1 trillion to $3.4 trillion annually by 2030, according to the World Bank.

There is a requirement for a new and natural antibiotic that can effectively combat these harmful bacteria. The human microbiota have demonstrated distinct and promising structures that can play a vital role in addressing this problem. In this particular scenario, it was necessary to present the existing literature on peptides derived from these bacteria, which paves the path for future research. Here, we effectively addressed this information gap by meticulously collecting and analysing a significant number of crucial peptides from the human microbiota, as well as exploring their potential biological functions in relation to human health. We also presented the mode of action of the majority of the peptides, along with a structural description where necessary. We have demonstrated that peptides exhibit not just antibacterial properties, but also powerful activity in the context of inflammation and cancer. This paves the door for further study to comprehensively explore the potential of these peptides not only as antimicrobial agents, but also in addressing various other human disorders. Acquiring this valuable information is essential for uncovering new molecular formations originating from the human microbiota, which may lead to a diverse array of metabolites with different biological effects. These findings not only improve our understanding of microbial ecology but also open up new possibilities for therapeutic approaches and the formulation of medications.

6 Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

7 Conflicts of interest

There are no conflicts to declare.

8 Acknowledgements

This research was supported by the Bio and Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2024-00352229) and the National Research Foundation (NRF) of Korea (NRF-2021R1A2C1004958 and NRF-2022R1A4A3022401).

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