Antimicrobial peptides: Opportunities and challenges in overcoming resistance.

Antibiotic resistance represents a global health threat, challenging the efficacy of traditional antimicrobial agents and necessitating innovative approaches to combat infectious diseases. Among these alternatives, antimicrobial peptides have emerged as promising candidates against resistant pathogens. Unlike traditional antibiotics with only one target, these peptides can use different mechanisms to destroy bacteria, with low toxicity to mammalian cells compared to many conventional antibiotics. Antimicrobial peptides (AMPs) have encouraging antibacterial properties and are currently employed in the clinical treatment of pathogen infection, cancer, wound healing, cosmetics, or biotechnology. This review summarizes the mechanisms of antimicrobial peptides against bacteria, discusses the mechanisms of drug resistance, the limitations and challenges of AMPs in peptide drug applications for combating drug-resistant bacterial infections, and strategies to enhance their capabilities.

Milk-derived extracellular vesicles functionalized with anti-tumour necrosis factor-α nanobody and anti-microbial peptide alleviate ulcerative colitis in mice.

Ulcerative colitis (UC) manifests clinically with chronic intestinal inflammation and microflora dysbiosis. Although biologics can effectively control inflammation, efficient delivery to the colon and colon epithelial cells remains challenging. Milk-derived extracellular vesicles (EV) show promise as an oral delivery tool, however, the ability to load biologics into EV presents challenges to therapeutic applications. Here, we demonstrate that fusing cell-penetrating peptide (TAT) to green fluorescent protein (GFP) enabled biologics loading into EV and protected against degradation in the gastrointestinal environment in vitro and in vivo after oral delivery. Oral administration of EV loaded with anti-tumour necrosis factor-α (TNF-α) nanobody (VHHm3F) (EVVHH) via TAT significantly reduced tissue TNF-α levels and alleviated pathologies in mice with acute UC, compared to VHH alone. In mice with chronic UC, simultaneously introducing VHH and an antimicrobial peptide LL37 into EV (EVLV), then administering orally improved intestinal barrier, inflammation and microbiota balance, resulted in relief of UC-induced depression and anxiety. Collectively, we demonstrated that oral delivery of EVLV effectively alleviated UC in mice and TAT efficiently loaded biologics into EV to confer protection from degradation in the gastrointestinal tract. This therapeutic strategy is promising for UC and is a simple and generalizable approach towards drug-loaded orally-administrable EV treatment for other diseases.

An Overview of Frog Skin-Derived Esc Peptides: Promising Multifunctional Weapons against Pseudomonas aeruginosa-Induced Pulmonary and Ocular Surface Infections.

Antimicrobial resistance is a silent pandemic harming human health, and Pseudomonas aeruginosa is the most common bacterium responsible for chronic pulmonary and eye infections. Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics. In this review, the in vitro/in vivo activities of the frog skin-derived AMP Esc(1-21) are shown. Esc(1-21) rapidly kills both the planktonic and sessile forms of P. aeruginosa and stimulates migration of epithelial cells, likely favoring repair of damaged tissue. However, to undertake preclinical studies, some drawbacks of AMPs (cytotoxicity, poor biostability, and limited delivery to the target site) must be overcome. For this purpose, the stereochemistry of two amino acids of Esc(1-21) was changed to obtain the diastereomer Esc(1-21)-1c, which is more stable, less cytotoxic, and more efficient in treating P. aeruginosa-induced lung and cornea infections in mouse models. Incorporation of these peptides (Esc peptides) into nanoparticles or immobilization to a medical device (contact lens) was revealed to be an effective strategy to ameliorate and/or to prolong the peptides' antimicrobial efficacy. Overall, these data make Esc peptides encouraging candidates for novel multifunctional drugs to treat lung pathology especially in patients with cystic fibrosis and eye dysfunctions, characterized by both tissue injury and bacterial infection.

[Progress of researches on the antiparasitic activity of antimicrobial peptide LL-37].

Parasitic diseases caused by protozoan and helminth infections are still widespread across the world, notably in tropical and subtropical areas, which threaten the children and adult health. Long-term use of anti-parasitic drugs may result in reduced drug susceptibility and even drug resistance. Antimicrobial peptides have been demonstrated to inhibit parasite growth and development, which has potential antiparasitic values. LL-37, the only human antimicrobial peptide in the cathelicidin family, has been widely investigated. This paper reviews the progress of researches on the antiparasitic activity of LL-37, and discusses the prospects of LL-37 in the research of parasites.

Combating Antimicrobial Resistance by Employing Antimicrobial Peptides: Immunomodulators and Therapeutic Agents against Infectious Diseases.

The rising prevalence of multiple-drug-resistant pathogens poses a formidable challenge to conventional antimicrobial treatments. The inability of potent antibiotics to combat these "superbugs" underscores the pressing need for alternative therapeutic agents. Antimicrobial peptides (AMPs) represent an alternative class of antibiotics. AMPs are essential immunomodulatory molecules that are found in various organisms. They play a pivotal role in managing microbial ecosystems and bolstering innate immunity by targeting and eliminating invading microorganisms. AMPs also have applications in the agriculture sector by combating animal as well as plant pathogens. AMPs can be exploited for the targeted therapy of various diseases and can also be used in drug-delivery systems. They can be used in synergy with current treatments like antibiotics and can potentially lead to a lower required dosage. AMPs also have huge potential in wound healing and regenerative medicine. Developing AMP-based strategies with improved safety, specificity, and efficacy is crucial in the battle against alarming global microbial resistance. This review will explore AMPs' increasing applicability, their mode of antimicrobial activity, and various delivery systems enhancing their stability and efficacy.

Therapeutic potential of antimicrobial peptides against pathogenic protozoa.

Protozoal infections cause significant morbidity and mortality in humans and animals. The use of several antiprotozoal drugs is associated with serious adverse effects and resistance development, and drugs that are more effective are urgently needed. Microorganisms, mammalian cells and fluids, insects, and reptiles are sources of antimicrobial peptides (AMPs) that act against pathogenic microorganisms; these AMPs have been widely studied as a promising alternative therapeutic option to conventional antibiotics, aiming to treat infections caused by multidrug-resistant pathogens. One advantage of AMP molecules is their adaptability, as they can be easily fine-tuned for broad-spectrum or targeted activity by changing the amino acid residues in their sequence. Consequently, these variations in structural and physicochemical properties can alter the antimicrobial activities of AMPs and decrease resistance development. This article presents an overview of peptide activities against amebiasis, giardiasis, trichomoniasis, Chagas disease, leishmaniasis, malaria, and toxoplasmosis. AMPs and their analogs demonstrate great potential as therapeutics, with potent and selective activity, when compared with commercially available drugs, and hold the potential to act as new scaffolds for the development of novel anti-protozoal drugs.

Modified host defence peptide GF19 slows TNT-mediated spread of corneal herpes simplex virus serotype I infection.

Corneal HSV-1 infections are a leading cause of infectious blindness globally by triggering tissue damage due to the intense inflammation. HSV-1 infections are treated mainly with antiviral drugs that clear the infections but are inefficient as prophylactics. The body produces innate cationic host defence peptides (cHDP), such as the cathelicidin LL37. Various epithelia, including the corneal epithelium, express LL37. cHDPs can cause disintegration of pathogen membranes, stimulate chemokine production, and attract immune cells. Here, we selected GF17, a peptide containing the LL37 fragment with bioactivity but with minimal cytotoxicity, and added two cell-penetrating amino acids to enhance its activity. The resulting GF19 was relatively cell-friendly, inducing only partial activation of antigen presenting immune cells in vitro. We showed that HSV-1 spreads by tunneling nanotubes in cultured human corneal epithelial cells. GF19 given before infection was able to block infection, most likely by blocking viral entry. When cells were sequentially  exposed to viruses and GF19,  the infection was attenuated but not arrested, supporting the contention that the GF19 mode of action was to block viral entry. Encapsulation into silica nanoparticles allowed a more sustained release of GF19, enhancing its activity. GF19 is most likely suitable as a prevention rather than a virucidal treatment.

Recent advances in antimicrobial peptide-based therapy.

Antimicrobial peptides (AMPs) are a group of polypeptide chains that have the property to target and kill a myriad of microbial organisms including viruses, bacteria, protists, etc. The first discovered AMP was named gramicidin, an extract of aerobic soil bacteria. Further studies discovered that these peptides are present not only in prokaryotes but in eukaryotes as well. They play a vital role in human innate immunity and wound repair. Consequently, they have maintained a high level of intrigue among scientists in the field of immunology, especially so with the rise of antibiotic-resistant pathogens decreasing the reliability of antibiotics in healthcare. While AMPs have promising potential to substitute for common antibiotics, their use as effective replacements is barred by certain limitations. First, they have the potential to be cytotoxic to human cells. Second, they are unstable in the blood due to action by various proteolytic agents and ions that cause their degradation. This review provides an overview of the mechanism of AMPs, their limitations, and developments in recent years that provide techniques to overcome those limitations. We also discuss the advantages and drawbacks of AMPs as a replacement for antibiotics as compared to other alternatives such as synthetically modified bacteriophages, traditional medicine, and probiotics.

Combating bacterial infections with host defense peptides: Shifting focus from bacteria to host immunity.

The increasing prevalence of multidrug-resistant bacterial infections necessitates the exploration of novel paradigms for anti-infective therapy. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), have garnered extensive recognition as immunomodulatory molecules that leverage natural host mechanisms to enhance therapeutic benefits. The unique immune mechanism exhibited by certain HDPs that involves self-assembly into supramolecular nanonets capable of inducing bacterial agglutination and entrapping is significantly important. This process effectively prevents microbial invasion and subsequent dissemination and significantly mitigates selective pressure for the evolution of microbial resistance, highlighting the potential of HDP-based antimicrobial therapy. Recent advancements in this field have focused on developing bio-responsive materials in the form of supramolecular nanonets. A comprehensive overview of the immunomodulatory and bacteria-agglutinating activities of HDPs, along with a discussion on optimization strategies for synthetic derivatives, is presented in this article. These optimized derivatives exhibit improved biological properties and therapeutic potential, making them suitable for future clinical applications as effective anti-infective therapeutics.

Application Value of Antimicrobial Peptides in Gastrointestinal Tumors.

Gastrointestinal cancer is a common clinical malignant tumor disease that seriously endangers human health and lacks effective treatment methods. As part of the innate immune defense of many organisms, antimicrobial peptides not only have broad-spectrum antibacterial activity but also can specifically kill tumor cells. The positive charge of antimicrobial peptides under neutral conditions determines their high selectivity to tumor cells. In addition, antimicrobial peptides also have unique anticancer mechanisms, such as inducing apoptosis, autophagy, cell cycle arrest, membrane destruction, and inhibition of metastasis, which highlights the low drug resistance and high specificity of antimicrobial peptides. In this review, we summarize the related studies on antimicrobial peptides in the treatment of digestive tract tumors, mainly oral cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer. This paper describes the therapeutic advantages of antimicrobial peptides due to their unique anticancer mechanisms. The length, net charge, and secondary structure of antimicrobial peptides can be modified by design or modification to further enhance their anticancer effects. In summary, as an emerging cancer treatment drug, antimicrobial peptides need to be further studied to realize their application in gastrointestinal cancer diseases.

Short Antimicrobial Peptides: Therapeutic Potential and Recent Advancements.

There has been a lot of interest in antimicrobial peptides (AMPs) as potential next-generation antibiotics. They are components of the innate immune system. AMPs have broad-spectrum action and are less prone to resistance development. They show potential applications in various fields, including medicine, agriculture, and the food industry. However, despite the good activity and safety profiles, AMPs have had difficulty finding success in the clinic due to their various limitations, such as production cost, proteolytic susceptibility, and oral bioavailability. To overcome these flaws, a number of solutions have been devised, one of which is developing short antimicrobial peptides. Short antimicrobial peptides do have an advantage over longer peptides as they are more stable and do not collapse during absorption. They have generated a lot of interest because of their evolutionary success and advantageous properties, such as low molecular weight, selective targets, cell or organelles with minimal toxicity, and enormous therapeutic potential. This article provides an overview of the development of short antimicrobial peptides with an emphasis on those with ≤ 30 amino acid residues as a potential therapeutic agent to fight drug-resistant microorganisms. It also emphasizes their applications in many fields and discusses their current state in clinical trials.

Effective Healing of Staphylococcus aureus-Infected Wounds in Pig Cathelicidin Protegrin-1-Overexpressing Transgenic Mice.

Antimicrobial peptides (AMPs) are promising alternatives to existing treatments for multidrug-resistant bacteria-infected wounds. Therefore, the effect of protegrin-1 (PG1), a potent porcine AMP with broad-spectrum activity, on wound healing was evaluated. PG1-overexpressing transgenic mice were used as an in vivo model to evaluate its healing efficiency against Staphylococcus aureus-infected (106 colony forming units) wounds. We analyzed the wounds under four specific conditions in the presence or absence of antibiotic treatment. We observed the resolution of bacterial infection and formation of neo-epithelium in S. aureus-infected wounds of the mice, even without antibiotic treatment, whereas all wild-type mice with bacterial infection died within 8 to 10 days due to uncontrolled bacterial proliferation. Interestingly, the wound area on day 7 was smaller (p < 0.01) in PG1 transgenic mice than that in the other groups, including antibiotic-treated mice, suggesting that PG1 exerts biological effects other than bactericidal effect. Additionally, we observed that the treatment of primary epidermal keratinocytes with recombinant PG1 enhanced cell migration in in vitro scratch and cell migration assays. This study contributes to the understanding of broad-spectrum endogenous cathelicidins with potent antimicrobial activities, such as PG1, on wound healing. Furthermore, our findings suggest that PG1 is a potent therapeutic candidate for wound healing.

Recent Progress in the Characterization, Synthesis, Delivery Procedures, Treatment Strategies, and Precision of Antimicrobial Peptides.

Infectious diseases are constantly evolving to bypass antibiotics or create resistance against them. There is a piercing alarm for the need to improve the design of new effective antimicrobial agents such as antimicrobial peptides which are less prone to resistance and possess high sensitivity. This would guard public health in combating and overcoming stubborn pathogens and mitigate incurable diseases; however, the emergence of antimicrobial peptides' shortcomings ranging from untimely degradation by enzymes to difficulty in the design against specific targets is a major bottleneck in achieving these objectives. This review is aimed at highlighting the recent progress in antimicrobial peptide development in the area of nanotechnology-based delivery, selectivity indices, synthesis and characterization, their doping and coating, and the shortfall of these approaches. This review will raise awareness of antimicrobial peptides as prospective therapeutic agents in the medical and pharmaceutical industries, such as the sensitive treatment of diseases and their utilization. The knowledge from this development would guide the future design of these novel peptides and allow the development of highly specific, sensitive, and accurate antimicrobial peptides to initiate treatment regimens in patients to enable them to have accommodating lifestyles.

Exploring the arsenal of antimicrobial peptides: Mechanisms, diversity, and applications.

Antimicrobial peptides (AMPs) are essential for defence against pathogens in all living organisms and possessed activities against bacteria, fungi, viruses, parasites and even cancer cells. AMPs are short peptides containing 12-100 amino acids conferring a net positive charge and an amphiphilic property in most cases. Although, anionic AMPs also exist. AMPs can be classified based on the types of secondary structures, charge, hydrophobicity, amino acid composition, length, etc. Their mechanism of action usually includes a membrane disruption process through pore formation (three different models have been described, barrel-stave, toroidal or carpet model) but AMPs can also penetrate and impair intracellular functions. Besides their activity against pathogens, they have also shown immunomodulatory properties in complex scenarios through many different interactions. The aim of this review to summarize knowledge about AMP's and discuss the potential application of AMPs as therapeutics, the challenges due to their limitations, including their susceptibility to degradation, the potential generation of AMP resistance, cost, etc. We also discuss the current FDA-approved drugs based on AMPs and strategies to circumvent natural AMPs' limitations.

Antimicrobial Peptide Synergies for Fighting Infectious Diseases.

Antimicrobial peptides (AMPs) are essential elements of thehost defense system. Characterized by heterogenous structures and broad-spectrumaction, they are promising candidates for combating multidrug resistance. Thecombined use of AMPs with other antimicrobial agents provides a new arsenal ofdrugs with synergistic action, thereby overcoming the drawback of monotherapiesduring infections. AMPs kill microbes via pore formation, thus inhibitingintracellular functions. This mechanism of action by AMPs is an advantage overantibiotics as it hinders the development of drug resistance. The synergisticeffect of AMPs will allow the repurposing of conventional antimicrobials andenhance their clinical outcomes, reduce toxicity, and, most significantly,prevent the development of resistance. In this review, various synergies ofAMPs with antimicrobials and miscellaneous agents are discussed. The effect ofstructural diversity and chemical modification on AMP properties is firstaddressed and then different combinations that can lead to synergistic action,whether this combination is between AMPs and antimicrobials, or AMPs andmiscellaneous compounds, are attended. This review can serve as guidance whenredesigning and repurposing the use of AMPs in combination with other antimicrobialagents for enhanced clinical outcomes.

No country for old antibiotics! Antimicrobial peptides (AMPs) as next-generation treatment for skin and soft tissue infection.

In recent years, the unprecedented rise of bacterial antibiotic resistance together with the lack of adequate therapies have made the treatment of skin infections and chronic wounds challenging, urging the scientific community to focus on the development of new and more efficient treatment strategies. In this context, there is a growing interest in the use of natural molecules with antimicrobial features, capable of supporting wound healing i.e., antimicrobial peptides (AMPs), for the treatment of skin and soft tissue infections. In this review, we give a short overview of the bacterial skin infections as well as some of the classic treatments used for topical application. We then summarize the AMPs classes, stressing the importance of the appropriate selection of the peptides based on their characteristics and physicochemical properties in order to maximize the antibacterial efficacy of the therapeutic systems against multi-drug resistant pathogens. Additionally, the present paper provides a comprehensive and rigorous assessment of the latest clinical trials investigating the efficacy of AMPs in the treatment of skin and soft tissue infections, highlighting the relevant outcomes. Seeking to obtain novel and improved compounds with synergistic activity, while also decreasing some of the known side effects of AMPs, we present two employed strategies using AMPs: (i) AMPs-conjugated nanosystems for systemic and topical drug delivery systems and (ii) antibiotics-peptide conjugates as a strategy to overcome antibiotics resistance. Finally, an important property of some of the AMPs used in wound treatment is highlighted: their ability to help in wound healing by generally promoting cell proliferation and migration, and in some cases re-epithelialization and angiogenesis among others. Thus, as the pursuit of improvement is an ongoing effort, this work presents the advances made in the treatment of skin and soft tissue infections along with their advantages and limitations, while the still remaining challenges are addressed by providing future prospects and strategies to overcome them.

The Potent Antitumor Activity of Smp43 against Non-Small-Cell Lung Cancer A549 Cells via Inducing Membranolysis and Mitochondrial Dysfunction.

Research has been conducted to investigate the potential application of scorpion venom-derived peptides in cancer therapy. Smp43, a cationic antimicrobial peptide from Scorpio maurus palmatus venom, has been found to exhibit suppressive activity against the proliferation of multiple cancer cell lines. However, its impact on non-small-cell lung cancer (NSCLC) cell lines has not been previously investigated. This study aimed to determine the cytotoxicity of Smp43 towards various NSCLC cell lines, particularly A549 cells with an IC50 value of 2.58 µM. The results indicated that Smp43 was internalized into A549 cells through membranolysis and endocytosis, which caused cytoskeleton disorganization, a loss of mitochondrial membrane potential, an accumulation of reactive oxygen species (ROS), and abnormal apoptosis, cell cycle distribution, and autophagy due to mitochondrial dysfunction. Additionally, the study explored the in vivo protective effect of Smp43 in xenograft mice. The findings suggest that Smp43 has potential anticarcinoma properties exerted via the inducement of cellular processes related to cell membrane disruption and mitochondrial dysfunction.

Antimicrobial peptides as potential therapy for gastrointestinal cancers.

Since conventional therapy faces limitations in the field of different cancers as well as gastrointestinal cancers, that decrease the survival rate of patients, there is an urgent need to find new effective therapeutic approaches without the adverse effects of the traditional agents. Antimicrobial peptides (AMPs) attract much attention and are well known for their role in innate immunity. These peptides, in addition to their antimicrobial activity, exhibit strong anticancer potential against various types of malignancy. AMPs specifically target tumor cells and have selective toxicity for these cells without affecting normal cells. Here we aim to comprehensively overview the current knowledge in the field of using AMPs as novel therapeutic agents for gastrointestinal cancer.

Therapeutic Peptides for Treatment of Lung Diseases: Infection, Fibrosis, and Cancer.

Various lung diseases endanger people's health. Side effects and pharmaceutical resistance complicate the treatment of acute lung injury, pulmonary fibrosis, and lung cancer, necessitating the development of novel treatments. Antimicrobial peptides (AMPs) are considered to serve as a viable alternative to conventional antibiotics. These peptides exhibit a broad antibacterial activity spectrum as well as immunomodulatory properties. Previous studies have shown that therapeutic peptides including AMPs had remarkable impacts on animal and cell models of acute lung injury, pulmonary fibrosis, and lung cancer. The purpose of this paper is to outline the potential curative effects and mechanisms of peptides in the three types of lung diseases mentioned above, which may be used as a therapeutic strategy in the future.