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Antimicrobial peptides (AMPs) are regarded as a new generation of antibiotics. Besides antimicrobial activity, AMPs also have antibiofilm, immune-regulatory, and other activities. Exploring the mechanism of action of AMPs may help in the modification and development of AMPs. Many studies were conducted on the mechanism of AMPs. The present review mainly summarizes the research status on the antimicrobial, anti-inflammatory, and antibiofilm properties of AMPs. This study not only describes the mechanism of cell wall action and membrane-targeting action but also includes the transmembrane mechanism of intracellular action and intracellular action targets. It also discusses the dual mechanism of action reported by a large number of investigations. Antibiofilm and anti-inflammatory mechanisms were described based on the formation of biofilms and inflammation. This study aims to provide a comprehensive review of the multiple activities and coordination of AMPs in vivo, and to fully understand AMPs to realize their therapeutic prospect.

Host defence peptides (HDPs) are integral components of innate immunity across all living organisms. These peptides can exert direct antibacterial effects, targeting planktonic cells (referred to as antimicrobial peptides), and exhibit antibiofilm (referred to as antibiofilm peptides), antiviral, antifungal and host-directed immunomodulatory activities. In this Review, we discuss how the complex functional attributes of HDPs provide many opportunities for the development of antimicrobial therapeutics, focusing particularly on their emerging antibiofilm properties. The mechanisms of action of antibiofilm peptides are compared and contrasted with those of antimicrobial peptides. Furthermore, obstacles for the practical translation of candidate peptides into therapeutics and the potential solutions are discussed. Critically, HDPs have the value-added assets of complex functional attributes, particularly antibiofilm and anti-inflammatory activities and their synergy with conventional antibiotics.In this Review, Hancock, Alford and Haney discuss how the complex functional attributes of host defence peptides provide many opportunities for the development of antimicrobial therapeutics, focusing on their emerging antibiofilm properties.

Peptides from frogs are promising antibiotic candidates.Frog-derived synthetic peptides selectively targeted Gram-negative pathogens, sparing beneficial microbiota and human cells.Structure-guided modifications improved the antimicrobial potency by optimizing hydrophobicity and net charge.Lead peptides effectively reduced bacterial loads in murine models of Pseudomonas aeruginosa and Acinetobacter baumannii infections without toxicity. Novel antibiotics are urgently needed since bacteria are becoming increasingly resistant to existing antimicrobial drugs. Furthermore, available antibiotics are broad spectrum, often causing off-target effects on host cells and the beneficial microbiome. To overcome these limitations, we used structure-guided design to generate synthetic peptides derived from Andersonin-D1, an antimicrobial peptide (AMP) produced by the odorous frog Odorrana andersonii. We found that both hydrophobicity and net charge were critical for its bioactivity, enabling the design of novel, optimized synthetic peptides. These peptides selectively targeted Gram-negative pathogens in single cultures and complex microbial consortia, showed no off-target effects on human cells or beneficial gut microbes, and did not select for bacterial resistance. Notably, they also exhibited in vivo activity in two preclinical murine models. Overall, we present synthetic peptides that selectively target pathogenic infections and offer promising preclinical antibiotic candidates. [Display omitted] Synthetic peptides, inspired by the natural defenses of amphibians, demonstrate selective activity against Gram-negative pathogens while sparing the gut microbiota and Gram-positive strains. Rationally designed peptides showed remarkable potency, exhibiting no signs of resistance or toxicity. These results underscore the potential of peptide-based antibiotics to tackle multidrug-resistant bacterial infections. Peptides represent highly promising scaffolds for drug development, offering tunable properties and versatility regarding their targets. Synthetic peptides are at the forefront of innovation in combating antibiotic resistance due to their modular nature, which enables precise design optimization. Currently in the preclinical phase [Technology Readiness Level (TRL) 3 or 4], these peptide molecules have shown robust efficacy in both in vitro and animal models, underscoring their potential as next-generation therapeutics. Recent advancements in rational peptide design, enhanced by machine learning and structure-guided approaches, are significantly improving antimicrobial peptide (AMP) potency, stability, and selectivity. Narrow-spectrum AMPs, designed to target specific pathogens, not only reduce the risk of antimicrobial resistance, but also help preserve the microbiome. Furthermore, consortia-based experiments evaluating peptides in complex bacterial communities are refining their application against multidrug-resistant infections. With continuous investment and technological innovation, AMPs are on track to enter clinical trials within the next decade. Addressing scalability and regulatory challenges will be critical to unlocking their full potential as precision-based therapies, ultimately providing an adaptable and effective solution for tackling resistant infections.

Antimicrobial peptides (AMPs) are emerging as a promising alternative to traditional antibiotics due to their ability to disturb bacterial membranes and/or their intracellular processes, offering a potential solution to the growing problem of antimicrobial resistance. AMP effectiveness is governed by factors such as net charge, hydrophobicity, and the ability to form amphipathic secondary structures. When properly balanced, these characteristics enable AMPs to selectively target bacterial membranes while sparing eukaryotic cells. This review focuses on the roles of positive charge, hydrophobicity, and structure in influencing AMP activity and toxicity, and explores strategies to optimize them for enhanced therapeutic potential. We highlight the delicate balance between these properties and how various modifications, including amino acid substitutions, peptide tagging, or lipid conjugation, can either enhance or impair AMP performance. Notably, an increase in these parameters does not always yield the best results; sometimes, a slight reduction in charge, hydrophobicity, or structural stability improves the overall AMP therapeutic potential. Understanding these complex interactions is key to developing AMPs with greater antimicrobial activity and reduced toxicity, making them viable candidates in the fight against antibiotic-resistant bacteria.

Despite the great strides in healthcare during the last century, some challenges still remained unanswered. The development of multi-drug resistant bacteria, the alarming growth of fungal infections, the emerging/re-emerging of viral diseases are yet a worldwide threat. Since the discovery of natural antimicrobial peptides able to broadly hit several pathogens, peptide-based therapeutics have been under the lenses of the researchers. This review aims to focus on synthetic peptides and elucidate their multifaceted mechanisms of action as antiviral, antibacterial and antifungal agents. Antimicrobial peptides generally affect highly preserved structures, e.g., the phospholipid membrane via pore formation or other constitutive targets like peptidoglycans in Gram-negative and Gram-positive bacteria, and glucan in the fungal cell wall. Additionally, some peptides are particularly active on biofilm destabilizing the microbial communities. They can also act intracellularly, e.g., on protein biosynthesis or DNA replication. Their intracellular properties are extended upon viral infection since peptides can influence several steps along the virus life cycle starting from viral receptor-cell interaction to the budding. Besides their mode of action, improvements in manufacturing to increase their half-life and performances are also taken into consideration together with advantages and impairments in the clinical usage. Thus far, the progress of new synthetic peptide-based approaches is making them a promising tool to counteract emerging infections.

Antimicrobial peptides (AMPs) are molecules with an amphipathic structure that enables them to interact with bacterial membranes. This interaction can lead to membrane crossing and disruption with pore formation, culminating in cell death. They are produced naturally in various organisms, including humans, animals, plants and microorganisms. In higher animals, they are part of the innate immune system, where they counteract infection by bacteria, fungi, viruses and parasites. AMPs can also be designed de novo by bioinformatic approaches or selected from combinatorial libraries, and then produced by chemical or recombinant procedures. Since their discovery, AMPs have aroused interest as potential antibiotics, although few have reached the market due to stability limits or toxicity. Here, we describe the development phase and a number of clinical trials of antimicrobial peptides. We also provide an update on AMPs in the pharmaceutical industry and an overall view of their therapeutic market. Modifications to peptide structures to improve stability in vivo and bioavailability are also described.

The development of novel antimicrobial peptides (AMPs) with broad-spectrum activity represents a promising strategy to overcome multidrug resistance in pathogenic bacteria. In this study, we investigated the antimicrobial activity of three designed peptides—R44KS*, V31KS*, and R23FS*—engineered to incorporate an amyloidogenic fragment from the S1 protein of Staphylococcus aureus and one or two cell-penetrating peptide (CPP) fragments to enhance cellular uptake. The antimicrobial efficacy of these peptides and their combinations was assessed against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Bacillus cereus. The results demonstrated that all three peptides exhibited significant antibacterial activity in a concentration-dependent manner, with R44KS* being the most potent. Peptide combinations, particularly V31KS*/R23FS* and R44KS*/V31KS*, showed enhanced inhibitory effects and reduced minimum inhibitory concentrations (MICs), suggesting synergistic or additive interactions. Fractional inhibitory concentration index (FICI) analysis confirmed that most combinations exhibited synergy or additive effects. These findings highlight the potential of CPP-modified peptides as antimicrobial agents and underscore the importance of optimizing peptide combinations for therapeutic applications.

The outburst of microbial resistance to antibiotics creates the need for new sources of active compounds for the treatment of pathogenic microorganisms. Marine microalgae are of particular interest in this context because they have developed tolerance and defense strategies to resist the exposure to pathogenic bacteria, viruses, and fungi in the aquatic environment. Although antimicrobial activities have been reported for some microalgae, natural algal bioactive peptides have not been described yet. In this work, acid extracts from the microalga Tetraselmis suecica with antibacterial activity were analyzed, and de novo sequences of peptides were determined. Synthetic peptides and their alanine and lysine analogs allowed identifying key residues and increasing their antibacterial activity. Additionally, it was determined that the localization of positive charges within the peptide sequence influences the secondary structure with tendency to form an alpha helical structure.

Antimicrobial resistance (AMR) is a global public health concern that is becoming a ‘silent’ pandemic. Novel treatment strategies are urgently needed to counteract this growing threat. To this end, Ageitos et al. leverage the natural antibacterial armamentarium of frogs to develop novel optimized synthetic peptides selective against Gram-negative pathogens. Antimicrobial resistance (AMR) is a global public health concern that is becoming a ‘silent’ pandemic. Novel treatment strategies are urgently needed to counteract this growing threat. To this end, Ageitos et al. leverage the natural antibacterial armamentarium of frogs to develop novel optimized synthetic peptides selective against Gram-negative pathogens.

Peptides derived from non-immune proteins showed potent in vitro antimicrobial activity.Nearly 90% of peptides tested exhibited immunomodulatory effects.Lead peptides displayed anti-infective efficacy in preclinical mouse models, effectively reducing infections. Encrypted peptides (EPs) have been recently described as a new class of antimicrobial molecules. They have been found in numerous organisms and have been proposed to have a role in host immunity and as alternatives to conventional antibiotics. Intriguingly, many of these EPs are found embedded in proteins unrelated to the immune system, suggesting that immunological responses extend beyond traditional host immunity proteins. To test this idea, we synthesized and analyzed representative peptides derived from non-immune human proteins for their ability to exert antimicrobial and immunomodulatory properties. Most of the tested peptides from non-immune proteins, derived from structural proteins as well as proteins from the nervous and visual systems, displayed potent in vitro antimicrobial activity. These molecules killed bacterial pathogens by targeting their membrane, and those originating from the same region of the body exhibited synergistic effects when combined. Beyond their antimicrobial properties, nearly 90% of the peptides tested exhibited immunomodulatory effects, modulating inflammatory mediators, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). Moreover, eight of the peptides identified, collagenin-3 and 4, zipperin-1 and 2, and immunosin-2, 3, 12, and 13, displayed anti-infective efficacy in two different preclinical mouse models, reducing bacterial infections by up to four orders of magnitude. Altogether, our results support the hypothesis that peptides from non-immune proteins may have a role in host immunity. These results potentially expand our notion of the immune system to include previously unrecognized proteins and peptides that may be activated upon infection to confer protection to the host. [Display omitted] The exploration of encrypted peptides and their antimicrobial properties has progressed over nearly a decade, now achieving Technology Readiness Levels 3/4 in laboratory settings. While these advances are promising, significant challenges must be addressed before full-scale implementation is feasible. The primary challenge lies in experimentally validating the in vivo expression and cleavage of parent proteins into encrypted peptides, either individually or in combination, at levels sufficient to exhibit antimicrobial activity. Key areas for further investigation include: (i) Overexpression studies: non-immune-related parent proteins should be overexpressed to determine whether the encrypted peptides exhibit the expected antimicrobial activity when produced at physiological levels. (ii) Knockout models: developing knockout models lacking the parent proteins of encrypted peptides could provide direct evidence of their functional roles by observing whether bacterial proliferation increases in their absence. (iii) In vivo experiments: using knockout mouse strains in in vivo experiments could reveal whether these animals show increased susceptibility to pathogenic infections, thereby validating the protective role of these peptides. Additionally, these peptides can be further explored and chemically modified to create more stable derivatives for direct application in clinical infection scenarios. However, transitioning from laboratory research to practical applications will require addressing key challenges, including optimizing peptide stability, bioavailability, and safety. Encrypted peptides derived from non-immune proteins exhibit potent antimicrobial and immunomodulatory properties. These peptides effectively kill bacterial pathogens, modulate immune mediators, and show anti-infective efficacy in preclinical models. The findings suggest that host immunity extends beyond traditional immune proteins, potentially broadening our current understanding of the immune system.