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In recent years, multidrug-resistant pathogenic microorganisms (MDROs) have emerged as a severe threat to human health, exhibiting robust resistance to traditional antibiotics. This has created a formidable challenge in modern medicine as we grapple with limited options to combat these resilient bacteria. Despite extensive efforts by scientists to develop new antibiotics targeting these pathogens, the quest for novel antibacterial molecules has become increasingly arduous. Fortunately, nature offers a potential solution in the form of cationic antimicrobial peptides (AMPs) and their synthetic counterparts. AMPs, naturally occurring peptides, have displayed promising efficacy in fighting bacterial infections by disrupting bacterial cell membranes, hindering their survival and reproduction. These peptides, along with their synthetic mimics, present an exciting alternative in combating antibiotic resistance. They hold the potential to emerge as a formidable tool against MDROs, offering hope for improved strategies to protect communities. Extensive research has explored the diversity, history, and structure-properties relationship of AMPs, investigating their amphiphilic nature for membrane disruption and mechanisms of action. However, despite their therapeutic promise, AMPs face several documented limitations. Among these challenges, poor pharmacokinetic properties stand out, impeding the attainment of therapeutic levels in the body. Additionally, some AMPs exhibit toxicity and susceptibility to protease cleavage, leading to a short half-life and reduced efficacy in animal models. These limitations pose obstacles in developing effective treatments based on AMPs. Furthermore, the high manufacturing costs associated with AMPs could significantly hinder their widespread use. In this review, we aim to present experimental and theoretical insights into different AMPs, focusing specifically on antibacterial peptides (ABPs). Our goal is to offer a concise overview of peptide-based drug candidates, drawing from a wide array of literature and peer-reviewed studies. We also explore recent advancements in AMP development and discuss the challenges researchers face in moving these molecules towards clinical trials. Our main objective is to offer a comprehensive overview of current AMP and ABP research to guide the development of more precise and effective therapies for bacterial infections.

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Leguminous crops are vital to sustainable agriculture due to their ability to fix atmospheric nitrogen, improving soil fertility and reducing the need for synthetic fertilizers. Additionally, they are an excellent source of protein for both human consumption and animal feed. Antimicrobial peptides (AMPs), found in various leguminous seeds, exhibit broad-spectrum antimicrobial activity through diverse mechanisms, including interaction with microbial cell membranes and interference with cellular processes, making them valuable for enhancing crop resilience and food safety. In the field of plant sciences, computational biology methods have been instrumental in the discovery and optimization of AMPs. These methods enable rapid exploration of sequence space and the prediction of AMPs using deep learning technologies. Optimizing AMP annotations through computational design offers a strategic approach to enhance efficacy and minimize potential side effects, providing a viable alternative to conventional antimicrobial agents. However, the presence of overlapping sequences across multiple databases poses a challenge for creating a reliable dataset for AMP prediction. To address this, we conducted a comprehensive analysis of sequence redundancy across various AMP databases. These databases encompass a wide range of AMPs from different sources and with specific functions, including both naturally occurring and artificially synthesized AMPs. Our analysis revealed significant overlap, underscoring the need for a non-redundant AMP sequence database. We present the development of a new database that consolidates unique AMP sequences derived from leguminous seeds, aiming to create a more refined dataset for the binary classification and prediction of plant-derived AMPs. This database will support the advancement of sustainable agricultural practices by enhancing the use of plant-based AMPs in agroecology, contributing to improved crop protection and food security.

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The overuse of traditional antibiotics has resulted in bacterial resistance and seriously compromised the therapeutic efficacy of traditional antibiotics, making the exploration of new antimicrobials particularly important. Several studies have shown that bioactive peptides have become an important source of new antimicrobial drugs due to their broad-spectrum antibacterial action and lack of susceptibility to resistance. In this study, a novel bioactive peptide Nigrosin-6VL was characterised from the skin secretion of the golden cross band frog, Odorrana andersonii, by using the 'shotgun' cloning strategy. Modifications on the Rana Box of Nigrosin-6VL revealed its critical role in antimicrobial functions. The peptide analogue, 2170-2R, designed to preserve the Rana Box structure while enhancing cationicity, exhibited improved therapeutic efficacy, particularly against Gram-negative bacteria, with a therapeutic value of 45.27. Synergistic studies demonstrated that 2170-2R inherits the synergistic antimicrobial activities of the parent peptides and effectively enhances the antimicrobial capacity of cefepime and gentamicin against both planktonic cells and biofilms. Specifically, 2170-2R can synergise effectively with cefepime and gentamicin against different strains of P. aeruginosa biofilms. Consequently, 2170-2R holds promise as a potent antimicrobial agent developed to combat infections induced by Pseudomonas aeruginosa.

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Aquaculture is a prosperous economic sector threatened by viral infections. Among the viruses threatening fish culture, Betanodavirus (NNV) is extremely important in the Mediterranean Sea affecting to highly traded species as European sea bass. In this context, application of antimicrobial peptides (AMPs) has arisen as a potential biotechnological tool. The aim of this work was to evaluate the therapeutic application of two European sea bass-derived AMPs, NK-lysin (Nkl) and dicentracin (Dic), against NNV infections. Synthetic Dic peptide was able to significantly reduce NNV-induced mortalities while Nkl failed to do so. Although neither Dic nor Nkl peptides were able to alter the transcriptional levels of NNV and the number of infected cells, Nkl seemed to increase the viral load per cell. Interestingly, both Nkl and Dic peptides showed immunomodulatory roles. For instance, our data revealed an interplay among different AMPs, at both gene and protein levels. Otherwise, Nkl and Dic peptides provoked an anti-inflammatory balance upon NNV infection, as well as the recruitment of macrophages and B cells to the target site of the infection, the brain. In conclusion, Dic can be proposed as a therapeutic candidate to combat NNV.

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As the clinical application of antibiotics for bacterial skin infections in companion animals becomes increasingly prevalent, the issue of bacterial resistance has become more pronounced. Antimicrobial peptides, as a novel alternative to traditional antibiotics, have garnered widespread attention. In our study, synthetic peptides ADD-A and CBD3-ABU were tested against Staphylococcus pseudintermedius skin infections in KM mice. ADD-A was applied topically and through intraperitoneal injection, compared with control groups and treatments including CBD3-ABU, ampicillin sodium, and saline. Wound contraction, bacterial counts and histology were assessed on days 3 and 11 post-infection. ADD-A and ampicillin treatments significantly outperformed saline in wound healing (p < 0.0001 and p < 0.001, respectively). ADD-A also showed a markedly lower bacterial count than ampicillin (p < 0.0001). Histologically, ADD-A-applied wounds had better epidermal continuity and a thicker epidermis than normal, with restored follicles and sebaceous glands. ADD-A's effectiveness suggests it as a potential alternative to antibiotics for treating skin infections in animals.

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Antimicrobial resistance poses a significant global health threat, necessitating innovative approaches for combatting it. This review explores various mechanisms of antimicrobial resistance observed in various strains of bacteria. We examine various strategies, including antimicrobial peptides (AMPs), novel antimicrobial materials, drug delivery systems, vaccines, antibody therapies, and non-traditional antibiotic treatments. Through a comprehensive literature review, the efficacy and challenges of these strategies are evaluated. Findings reveal the potential of AMPs in combating resistance due to their unique mechanisms and lower propensity for resistance development. Additionally, novel drug delivery systems, such as nanoparticles, show promise in enhancing antibiotic efficacy and overcoming resistance mechanisms. Vaccines and antibody therapies offer preventive measures, although challenges exist in their development. Non-traditional antibiotic treatments, including CRISPR-Cas systems, present alternative approaches to combat resistance. Overall, this review underscores the importance of multifaceted strategies and coordinated global efforts to address antimicrobial resistance effectively.

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Antimicrobial peptides (AMPs), short peptides with diverse functions, effectively target and combat various organisms. The widespread misuse of chemical antibiotics has led to increasing microbial resistance. Due to their low drug resistance and toxicity, AMPs are considered promising substitutes for traditional antibiotics. While existing deep learning technology enhances AMP generation, it also presents certain challenges. Firstly, AMP generation overlooks the complex interdependencies among amino acids. Secondly, current models fail to integrate crucial tasks like screening, attribute prediction and iterative optimization. Consequently, we develop a integrated deep learning framework, Diff-AMP, that automates AMP generation, identification, attribute prediction and iterative optimization. We innovatively integrate kinetic diffusion and attention mechanisms into the reinforcement learning framework for efficient AMP generation. Additionally, our prediction module incorporates pre-training and transfer learning strategies for precise AMP identification and screening. We employ a convolutional neural network for multi-attribute prediction and a reinforcement learning-based iterative optimization strategy to produce diverse AMPs. This framework automates molecule generation, screening, attribute prediction and optimization, thereby advancing AMP research. We have also deployed Diff-AMP on a web server, with code, data and server details available in the Data Availability section.

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Ophthalmia neonatorum is a microbial contraction, damaging eyesight, occurring largely among neonates. Infants are particularly vulnerable to bacterial infections acquired during birth from infected mothers, especially from Neisseria gonorrhoeae and Chlamydia trachomatis. Over the decades, N. gonorrhoeae is alarmingly developing a resistance to most antibiotics currently prescribed. To counter this challenge, it is imperative to find potent and cost-effective therapeutic agents for prophylaxis and treatment, to which the N. gonorrhoeae cannot easily develop resistance. This review showcases alternate therapies such as antimicrobial-fatty acids, -peptides, -nano-formulations etc., currently evident against N. gonorrhoeae-mediated ophthalmia neonatorum, which remains a major cause of ocular morbidity, blindness and even death among neonates in developing countries.

Gonorrhea is a sexually transmitted infection caused by the bacteria Neisseria gonorrhoeae. N. gonorrhoeae can infect a newborn's eyes during birth by an infected mother. These babies can develop redness, irritation and discomfort in the eye(s), a condition called ophthalmia neonatorum. This condition can lead to blindness. Antibiotics are used to treat N. gonorrhoeae infections, but in recent decades, it has been fast evolving to avoid the action of most antibiotics. This is known as antibiotic resistance. There is, therefore, an urgent need for easily accessible non-antibiotic therapies. In this article, various alternate therapies currently available to treat N. gonorrhoeae have been reviewed.

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The burden of bacterial wound infections has considerably increased due to antibiotic resistance to most of the currently available antimicrobial drugs. Herein, for the first time, a chemical coupling of two cationic N-aryl (pyridyl and aminocinnamyl) chitosan derivatives to antimicrobial peptide dendrimers (AMPDs) of different generations (first, second, and third) via thioether-haloacetyl reaction is reported. The new chitosan-AMPD conjugates show high selectivity by killing Pseudomonas aeruginosa and very low toxicity toward mammalian cells, as well as extremely low hemolysis to red blood cells. Electron microscopy reveals that the new chitosan derivatives coupled to AMPD destroy both the inner and outer membranes of Gram-negative P. aeruginosa. Moreover, chitosan-AMPD conjugates show synergetic effects within extremely low concentrations. The new chitosan-AMPD conjugates can be used as potent antimicrobial therapeutic agents, to eradicate pathogens such as those present in acute and chronic infected wounds.

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Antimicrobial peptides (AMPs) are promising molecules in diverse fields, including aquaculture. AMPs possess lytic effects on a wide range of pathogens, resulting in a potential replacement for traditional antimicrobials in aquaculture. In addition, they also have modulatory effects on host immune responses. Thus, the objective of this work was to evaluate the immunomodulatory capability of three known synthetic AMPs derived from European sea bass, NK-lysin (Nkl), hepcidin (Hamp), and dicentracin (Dic), in head-kidney cell suspensions from European sea bass and gilthead seabream. The tested peptides were neither cytotoxic for European sea bass nor gilthead seabream cells and failed to modulate the respiratory burst and phagocytosis activities. However, they modified the pattern of transcription of immune-related genes differently in both species. Peptides were able to promote the expression of marker genes for anti-inflammatory (il10), antiviral (mx, irf3), cell-mediated cytotoxicity (nccrp1, gzmb), and antibody responses (ighm) in European sea bass, with the Nkl peptide being the most effective. Contrary to this, the effects of those peptides on gilthead seabream mainly resulted in the suppression of immune responses. To conclude, European sea bass-derived peptides can be postulated as potential tools for immunostimulation in European sea bass fish farms, but more efforts are required for their universal use in other species.

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BACKGROUND: Previous studies of brown planthopper (BPH), Nilaparvata lugens, showed that carrying the plant pathogenic virus, rice ragged stunt virus (RRSV), enhanced the lethality of the entomopathogenic fungus, Metarhizium anisopliae (YTTR). The underlying mechanism for this was not established but a serine protease cascade was hypothesized to be involved. RESULTS: Two immune response genes, NlKPI and NlVenomase, were identified and shown to be involved. The synthesized double-strand RNA (dsRNA) techniques used in this study to explore gene function revealed that treatment with dsRNA to silence either gene led to a higher BPH mortality from M. anisopliae infection than the dsRNA control treatment. NlKPI and NlVenomase play vital roles in BPH immunity to defend against alien pathogens. Both genes participate in the immune response process of BPH against co-infection with RRSV and M. anisopliae YTTR by regulating the expression of antimicrobial peptides and phenoloxidase activity. CONCLUSION: Our study provided new targets for BPH biocontrol and laid a solid foundation for further research on the interaction of virus-insect-EPF (entomopathogenic fungus). © 2023 Society of Chemical Industry.

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Conventional wound infection treatments neither actively promote wound healing nor address the growing problem of antibacterial resistance. Antimicrobial peptides (AMPs) are natural defense molecules, released from host cells, which may be rapidly bactericidal, modulate host-immune responses, and/or act as endogenous mediators for wound healing. However, their routine clinical use has hitherto been hindered due to their instability in the wound environment. Here we describe an electrospun carrier system for topical application of pleurocidin, demonstrating sufficient AMP release from matrices to kill wound-associated pathogens including Acinetobacter baumannii and Pseudomonas aeruginosa. Pleurocidin can be incorporated into polyvinyl alcohol (PVA) fiber matrices, using coaxial electrospinning, without major drug loss with a peptide content of 0.7% w/w predicted sufficient to kill most wound associated species. Pleurocidin retains its activity on release from the electrospun fiber matrix and completely inhibits growth of two strains of A. baumannii (AYE; ATCC 17978) and other ESKAPE pathogens. Inhibition of P. aeruginosa strains (PAO1; NCTC 13437) is, however, matrix weight per volume dependent, with only larger/thicker matrices maintaining complete inhibition. The resulting estimation of pleurocidin release from the matrix reveals high efficiency, facilitating a greater AMP potency. Wound matrices are often applied in parallel or sequentially with the use of standard wound care with biocides, therefore the presence and effect of biocides on pleurocidin potency was tested. It was revealed that combinations displayed additive or modestly synergistic effects depending on the biocide and pathogens which should be considered during the therapy. Taken together, we show that electrospun, pleurocidin-loaded wound matrices have potential to be investigated for wound infection treatment.

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This study explores the effectiveness of the antineoplastic agent 5-FU in cancer cells by leveraging the unique properties of cationic antimicrobial peptides (CAMPs) and cell-penetrating peptides (CPPs). Traditional anticancer therapies face substantial limitations, including unfavorable pharmacokinetic profiles and inadequate specificity for tumor sites. These drawbacks often necessitate higher therapeutic agent doses, leading to severe toxicity in normal cells and adverse side effects. Peptides have emerged as promising carriers for targeted drug delivery, with their ability to selectively deliver therapeutics to cells expressing specific receptors. This enhances intracellular drug delivery, minimizes drug resistance, and reduces toxicity. In this research, we comprehensively evaluate the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of various AMPs and CPPs to gain insights into their potential as anticancer agents. The peptide synthesis involved a solid-phase synthesis using a Liberty Microwave Peptide Synthesizer. The peptide purity was confirmed via LC-MS and HPLC methods. For the ADMET screening, computational tools were employed, assessing parameters like absorption, distribution, metabolism, excretion, and toxicity. The cell lines A549 and UM-UC-5 were cultured and treated with 5-FU, CAMPs, and CPPs. The cell viability was measured using the MTT assay. The physicochemical properties analysis revealed favorable drug-likeness attributes. The peptides exhibited potential inhibitory activity against CYP3A4. The ADMET predictions indicated variable absorption and distribution characteristics. Furthermore, we assessed the effectiveness of these peptides alone and in combination with 5-FU, a widely used antineoplastic agent, in two distinct cancer cell lines, UM-UC-5 and A549. Our findings indicate that CAMPs can significantly reduce the cell viability in A549 cells, while CPPs exhibit promising results in UM-UC-5 cells. Understanding these multifaceted effects could open new avenues for antiviral and anticancer research. Further, experimental validation is necessary to confirm the mechanism of action of these peptides, especially in combination with 5-FU.

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[This corrects the article DOI: 10.3389/fchem.2022.840131.].

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(1) The global population is projected to reach a staggering 9.8 billion people by the year 2050, leading to major concerns about food security. The necessity to increase livestock production is inevitable. The black soldier fly (BSF) is known for its ability to consume a wide range of organic waste, and BSF larvae have already been used as a partial substitute for fishmeal. In contrast, the use of antibiotics in livestock feed for growth promotion and prophylaxis poses a severe threat to global health owing to antimicrobial resistance. Insect antimicrobial peptides (AMPs) have shown the potential to rapidly disrupt target bacterial membranes, making bacterial resistance to AMPs a less likely concern. (2) In this study, we explored various methods for stimulating AMP synthesis in BSF larvae and found that thermal injury effectively induced the production of various AMP types. Additionally, we investigated the activation of innate immune response pathways that lead to AMP production following thermal injury. (3) Interestingly, thermal injury treatment, although not involving bacteria, exhibited a similar response to that observed following Gram-positive bacterial infection in eliciting the expression of AMP genes. (4) Our findings offer support for the industrial use of BSF to enhance livestock production and promote environmental health.

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Changes in the structure and function of the microbiota are associated with various human diseases. These microbial changes can be mediated by antimicrobial peptides (AMPs), small peptides produced by the host and their microbiota, which play a crucial role in host-bacteria co-evolution. Thus, by studying AMPs produced by the microbiota (microbial AMPs), we can better understand the interactions between host and bacteria in microbiome homeostasis. Additionally, microbial AMPs are a new source of compounds against pathogenic and multi-resistant bacteria. Further, the growing accessibility to metagenomic and metatranscriptomic datasets presents an opportunity to discover new microbial AMPs. This review examines the structural properties of microbiota-derived AMPs, their molecular action mechanisms, genomic organization, and strategies for their identification in any microbiome data as well as experimental testing. Overall, we provided a comprehensive overview of this important topic from the microbial perspective.

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Golden pompano, Trachinotus ovatus, as a highly nutritious commercially valuable marine fish, has become one of the preferred species for many fish farmers due to its rapid growth, wide adaptability, and ease of feeding and management. However, with the expansion of aquaculture scale, bacterial and parasitic diseases have also become major threats to the golden pompano industry. This study, based on comparative genomics, shows the possibility of preferential evolution of freshwater fish over marine fish by analyzing the phylogenetic relationships and divergence times of 14 marine fish and freshwater fish. Furthermore, we identified antimicrobial peptide genes from 14 species at the genomic level and found that the number of putative antimicrobial peptides may be related to species evolution. Subsequently, we classified the 341 identified AMPs from golden pompano into 38 categories based on the classification provided by the APD3. Among them, TCP represented the highest proportion, accounting for 23.2% of the total, followed by scolopendin, lectin, chemokine, BPTI, and histone-derived peptides. At the same time, the distribution of AMPs in chromosomes varied with type, and covariance analysis showed the frequency of its repeat events. Enrichment analysis and PPI indicated that AMP was mainly concentrated in pathways associated with disease immunity. In addition, our transcriptomic data measured the expression of putative AMPs of golden pompano in 12 normal tissues, as well as in the liver, spleen, and kidney infected with Streptococcus agalactiae and skin infected with Cryptocaryon irritans. As the infection with S. agalactiae and C. irritans progressed, we observed tissue specificity in the number and types of responsive AMPs. Positive selection of AMP genes may participate in the immune response through the MAPK signaling pathway. The genome-wide identification of antimicrobial peptides in the golden pompano provided a complete database of potential AMPs that can contribute to further understanding the immune mechanisms in pathogens. AMPs were expected to replace traditional antibiotics and be developed into targeted drugs against specific bacterial and parasitic pathogens for more precise and effective treatment to improve aquaculture production.

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Our understanding of drug-microbe relationships has evolved from viewing microbes as mere drug producers to a dynamic, modifiable system where they can serve as drugs or targets of precision pharmacology. This review highlights recent findings on the gut microbiome, particularly focusing on four aspects of research: (i) drugs for bugs, covering recent strategies for targeting gut pathogens; (ii) bugs as drugs, including probiotics; (iii) drugs from bugs, including postbiotics; and (iv) bugs and drugs, discussing additional types of drug-microbe interactions. This review provides a perspective on future translational research, including efficient companion diagnostics in pharmaceutical interventions.

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Antimicrobial peptides (AMPs) have attracted considerable attention as potential substitutes for traditional antibiotics. In our previous research, a novel antimicrobial peptide YS12 derived from the Bacillus velezensis strain showed broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria. In this study, the fractional inhibitory concentration index (FICI) indicated that combining YS12 with commercial antibiotics produced a synergistic effect. Following these findings, the combination of YS12 with an antibiotic resulted in a faster killing effect against bacterial strains compared to the treatment with the peptide YS12 or antibiotic alone. The peptide YS12 maintained its antimicrobial activity under different physiological salts (Na+, Mg2+, and Fe3+). Most importantly, YS12 exhibited no cytotoxicity towards Raw 264.7 cells and showed low hemolytic activity, whereas positive control melittin indicated extremely high toxicity. In terms of mode of action, we found that peptide YS12 was able to bind with LPS through electrostatic interaction. The results from fluorescent measurement revealed that peptide YS12 damaged the integrity of the bacterial membrane. Confocal laser microscopy further confirmed that the localization of peptide YS12 was almost in the cytoplasm of the cells. Peptide YS12 also exhibited anti-inflammatory activity by reducing the release of LPS-induced pro-inflammatory mediators such as TNF-α, IL-1ß, and NO. Collectively, these properties strongly suggest that the antimicrobial peptide YS12 may be a promising candidate for treating microbial infections and inflammation.

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Vibrio harveyi is the primary pathogenic bacteria affecting Nibea albiflora aquaculture. In a previous phase, our laboratory intentionally exposed N. albiflora to V. harveyi and analyzed the outcomes using a combination of genome-wide association study (GWAS) and RNA-seq. The results revealed that the antimicrobial peptide NK-lysin (YdNkl-1) was a candidate gene for resistance to V. harveyi disease in N. albiflora. To investigate the role of the antimicrobial peptide NK-lysin in N. albiflora's antimicrobial immunity, we screened the YdNkl-1 gene from the transcriptome database. The full-length cDNA of YdNkl-1 gene is 508 bp, with an open reading frame (ORF) of 477 bp, encoding 158 amino acids. The deduced amino acid sequence of YdNkl-1 contains a signal peptide (1st-22nd amino acids) and a Saposin B domain (50th-124th amino acids), akin to mammalian NK-lysin. Phylogenetic tree analysis confirmed that the NK-lysin of teleost fish clustered into a single species, and YdNkl-1 was most closely related to Larimichthys crocea. Subcellular localization showed that YdNkl-1 was distributed in cytoplasm and nucleus of yellow drum kidney cells. Furthermore, YdNkl-1 mRNA transcripts were significantly up-regulated in the skin, gill, intestine, head-kidney, liver, and spleen after V. harveyi infection, suggesting a critical role in N. albiflora's defense against V. harveyi infection. Additionally, we purified and observed the YdNkl-1 protein, which exhibited a potent membrane-disrupting effect on V. harveyi, Pseudomonas plecoglossicida, Vibrio parahaemolyticus, Escherichia coli and Bacillus subtilis. These findings underscore the significance of NK-lysin in N. albiflora's resistance to V. harveyi infection and provide new insights into the crucial role of NK-lysin in the innate immunity of teleost fishes.

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