ABIO

General Introduction to Cationic Antimicrobial Peptides (CAPs)

Cationic Antimicrobial Peptides (CAPs), also commonly referred to as Anti Microbial Peptides (AMPs), are a diverse group of small, positively charged peptides that play a crucial role in the innate immune defense of virtually all living organisms [1]. Typically composed of 12 to 50 amino acids, these peptides are characterized by a net positive charge at physiological pH and an amphipathic structure that allows them to interact with and disrupt microbial membranes. CAPs are evolutionarily conserved across species, underscoring their fundamental importance in host defense mechanisms [1,2]. CAPs are produced by a wide variety of organisms including humans, animals, plants, and even certain bacteria and fungi [1]. In humans, they are expressed by epithelial cells, neutrophils, and other immune cells, and are particularly abundant at sites of host–microbe interaction such as the skin, respiratory tract, and gastrointestinal mucosa. Some of the best-known human CAPs include defensins and cathelicidins, notably the peptide LL-37 [1,3]. These molecules act not only as antimicrobial agents but also as modulators of immune responses, bridging the gap between innate and adaptive immunity. The growing interest in CAPs stems from their broad-spectrum activity against bacteria (both Gram-positive and Gram-negative), fungi, viruses, and even some protozoa [1,4]. Unlike conventional antibiotics, CAPs often kill microbes through membrane disruption and other mechanisms that are less prone to inducing resistance. This unique mode of action makes them attractive candidates in the fight against multidrug-resistant pathogens, which represent an escalating public health crisis worldwide.

Over the past two decades, extensive research has been devoted to characterizing the structure, function, and potential applications of CAPs. Their versatility includes not only direct antimicrobial activity but also anti-inflammatory, immunoregulatory, and wound-healing properties [1,4]. Despite these promising attributes, clinical translation of CAPs has been limited due to challenges such as peptide stability, toxicity at high concentrations, and cost of production. This article aims to provide a comprehensive overview of CAPs with a specific focus on their relevance to human medicine. We will examine their mechanisms of action, categorize the main types of CAPs under investigation, explore their clinical applications, review ongoing clinical trials, and discuss the challenges and future perspectives for their therapeutic use. The ultimate goal is to assess the viability of CAPs as next-generation antimicrobial agents in an era where antibiotic resistance poses a severe global threat.

Mechanisms of Action of Antimicrobial Peptides

Cationic Antimicrobial Peptides (CAPs) exhibit a range of mechanisms to eliminate or neutralize pathogenic microbes, with their primary mode of action targeting the structural integrity of microbial membranes [1]. Due to their amphipathic and cationic nature, CAPs preferentially bind to the negatively charged components of bacterial membranes, such as Lipo-PolySaccharides (LPS) in Gram-negative bacteria or teichoic acids in Gram-positive bacteria [1,3]. This electrostatic attraction facilitates the insertion of the peptide into the lipid bilayer, leading to membrane destabilization, pore formation, and ultimately cell lysis. Several models have been proposed to describe membrane disruption by CAPs, including the “barrel-stave,” “carpet,” and “toroidal pore” mechanisms [1,2]. In the barrel-stave model, peptides insert themselves perpendicularly into the membrane, forming a pore lined by the peptides. The carpet model suggests that CAPs cover the membrane surface and, upon reaching a threshold concentration, cause membrane disintegration in a detergent-like manner. The toroidal pore model is an intermediate mechanism where peptides induce membrane curvature, forming transient pores lined by both peptides and lipid head groups. Regardless of the exact mechanism, membrane perturbation leads to leakage of cytoplasmic contents and bacterial death [2,3].

Beyond their direct lytic action, many CAPs exert additional intracellular effects. After crossing the microbial membrane, some peptides can inhibit nucleic acid synthesis, protein synthesis, or enzymatic functions essential for microbial survival [4-6]. These secondary mechanisms may enhance the bactericidal efficacy of CAPs and reduce the likelihood of resistance development, as multiple bacterial targets are simultaneously affected. Notably, some CAPs also act synergistically with conventional antibiotics, increasing bacterial permeability and facilitating drug entry. CAPs are not only microbicidal but also play significant roles in modulating the host immune response. They can influence cytokine production, promote chemotaxis of immune cells, and enhance phagocytosis [4,5]. For instance, LL-37 has been shown to induce the release of Interleukin-8 (IL-8) and other proinflammatory mediators, while also exerting anti-inflammatory effects depending on the context and concentration. This dual rolecombining direct antimicrobial activity with immune regulationpositions CAPs as multifunctional agents in host defense [3]. An important advantage of CAPs is their relatively low tendency to induce microbial resistance [7,8]. Because they target conserved and essential features of microbial membranes and functions, the evolutionary cost for pathogens to develop resistance is high. However, emerging evidence suggests that some bacteria can develop partial resistance through modifications of membrane charge, expression of proteases that degrade CAPs, or increased efflux. Understanding these resistance mechanisms is essential for optimizing CAP design and ensuring long-term efficacy.

Typology of CAPs Studied in Human Medicine

Cationic Antimicrobial Peptides (CAPs) encompass a structurally and functionally diverse group of molecules. In human medicine, CAPs are typically classified into families based on their origin, structural motifs, and amino acid composition. The most prominent classes include defensins, cathelicidins, magainins, bactenecins, and several synthetic or engineered analogs. Each class presents unique properties that influence its therapeutic potential, such as spectrum of activity, stability, and immunomodulatory capacity [1,6]. Defensins are among the most well-studied endogenous human CAPs and are divided into two major subtypes: α-defensins and β-defensins. These peptides are rich in cysteine residues, which form disulfide bridges that stabilize a β-sheet structure. α-defensins are primarily produced by neutrophils (e.g., HNP1 to HNP-4), while β-defensins (e.g., hBD-1 to hBD-4) are secreted by epithelial cells [1,4,5]. These peptides display broad antimicrobial activity and are also implicated in immune signaling and chemotaxis [6]. Their relatively small size and stable structure make them attractive templates for drug design. Cathelicidins, particularly the human peptide LL-37, are linear α-helical CAPs with potent antimicrobial and immunomodulatory functions. LL37 is the only cathelicidin identified in humans and is produced by epithelial cells, neutrophils, and macrophages [1,2]. In addition to disrupting microbial membranes, LL-37 modulates inflammation, promotes wound healing, and neutralizes bacterial endotoxins. Its multifunctional nature has spurred the development of synthetic analogs with improved specificity and stability, such as OP-145 and GF-17 [2,3,5].

CAPs derived from other organisms have also attracted medical interest. Magainins, originally isolated from the skin of the African clawed frog (Xenopus laevis), are α-helical peptides that demonstrate broad-spectrum antimicrobial activity with low mammalian cytotoxicity. Similarly, bactenecins, found in bovine neutrophils, exhibit strong bactericidal effects against Gramnegative bacteria. These non-human peptides serve as important models for developing synthetic CAPs and peptidomimetics with enhanced pharmacological properties. To address limitations such as enzymatic degradation, narrow therapeutic windows, and toxicity, numerous synthetic and engineered CAPs have been developed [2-4]. Rational design approaches involve sequence optimization, incorporation of D-amino acids, peptide cyclization, and backbone modifications to improve stability and bioavailability. Peptidomimetics-molecules that mimic the biological activity of CAPs without being peptides-have also emerged as promising alternatives, offering increased resistance to proteolysis and lower immunogenicity. By studying native peptides and designing optimized derivatives, researchers aim to harness the therapeutic potential of CAPs while overcoming the pharmacokinetic and safety challenges that limit their clinical translation.

Clinical Applications Under Investigation or Development

The clinical potential of Cationic Antimicrobial Peptides (CAPs) has been increasingly explored in the context of infections that are difficult to treat with conventional antibiotics, particularly those involving multidrug-resistant organisms or biofilms. Their broadspectrum antimicrobial activity and immunomodulatory functions make them attractive candidates for a range of therapeutic applications in human medicine Table 1. Several CAPs and their synthetic analogs are being developed for topical, systemic, and localized use in infections of the skin, lungs, urinary tract, and medical devices. Skin and soft tissue infections are among the most advanced targets for CAP-based therapies. Conditions such as infected burns, chronic ulcers, and atopic dermatitis offer a favorable setting for the topical application of peptides, bypassing systemic toxicity concerns. Synthetic peptides like Pexiganan (a magainin analog) have been developed for diabetic foot ulcers and have completed phase III clinical trials. Similarly, omiganan, a synthetic indolicidin analog, has been investigated as a topical agent for catheter-associated infections and skin conditions complicated by bacterial colonization. These peptides not only reduce microbial burden but also promote wound healing and modulate local inflammation.

In pulmonary infections, particularly in diseases like Cystic Fibrosis (CF) and hospital-acquired pneumonia, CAPs have shown promise due to their ability to function in mucus-rich environments and retain activity against biofilm-embedded pathogens. The cathelicidin LL-37, for example, is found in airway secretions and contributes to innate lung defense. Inhalable formulations of CAPs are under investigation to deliver the peptides directly to the site of infection, enhancing efficacy while minimizing systemic exposure. Experimental therapies include nebulized or dry-powder forms designed to combat Pseudomonas aeruginosa and other resistant strains prevalent in CF patients. Urinary and genital tract infections, especially recurrent or catheter-associated types, are another focus of CAP development. The acidic and protease-rich environment of the urinary tract poses formulation challenges; however, modified CAPs with enhanced stability have shown efficacy in preclinical models. Certain peptides also exhibit antiviral activity, making them candidates for treating Sexually Transmitted Infections (STIs), including those caused by Herpes simplex virus or HIV. For example, CAPs have been incorporated into vaginal gels and microbicides to provide local protection against both bacterial and viral pathogens.

A rapidly evolving area of research involves the prevention of infections associated with medical devices such as catheters, endotracheal tubes, and orthopedic implants. CAPs can be immobilized onto biomaterial surfaces to prevent bacterial colonization and biofilm formation. Surface coatings with peptides like LL-37 or synthetic analogs can confer antimicrobial activity while preserving biocompatibility. These approaches are particularly relevant in intensive care settings, where deviceassociated infections are a major source of morbidity and mortality. Collectively, these clinical applications highlight the versatility of CAPs across multiple domains of human medicine. Their capacity to address unmet therapeutic needs-particularly where resistance or biofilms render antibiotics ineffective-makes them important tools in the development of next-generation antiinfectives. However, successful clinical translation will depend on overcoming formulation, delivery, and toxicity challenges, which remain significant in systemic and long-term applications.

Table 1: Clinical potential of cationic antimicrobial peptides.

Ongoing Clinical Trials and Preliminary Results 

Despite the strong preclinical evidence supporting the efficacy of Cationic Antimicrobial Peptides (CAPs), only a limited number have progressed to clinical trials [9-15]. However, the results of early-phase studies have been promising, particularly in topical and localized applications Table 2. These trials provide critical insights into the pharmacodynamics, safety profiles, and clinical efficacy of CAPs in human populations and help identify formulation and delivery challenges for systemic use [15]. One of the most studied CAPs in clinical development is pexiganan, a synthetic analog of magainin developed for the treatment of diabetic foot ulcers. In multiple phase II and III trials, pexiganan demonstrated comparable efficacy to oral antibiotics (e.g., ofloxacin) when used as a topical cream [10]. Although initial FDA approval was not granted due to lack of superiority, subsequent studies supported its safety and non-inferiority, leading to renewed interest in combination therapies or use in resistant infections. Pexiganan’s broad-spectrum activity, including effectiveness against Methicillin-Resistant Staphylococcus aureus (MRSA), supports its potential as a topical antimicrobial for chronic wound care.

Omiganan pentahydrochloride, a synthetic indolicidin derivative, has also been evaluated in clinical trials. It has undergone phase I and II studies for applications including prevention of catheter-associated infections, acne vulgaris, and rosacea [9- 12]. In these studies, omiganan was generally well-tolerated and showed moderate efficacy in reducing microbial colonization and inflammatory symptoms. However, some trials reported variable outcomes, possibly due to challenges in peptide penetration and local bioavailability. These mixed results underscore the need for optimized formulations and dosing strategies to maximize therapeutic benefit. A newer class of synthetic CAPs, including brilacidin, has shown promise in both antimicrobial and antiinflammatory roles [9-14]. Brilacidin has completed phase II trials for oral mucositis in cancer patients and for skin infections. It demonstrated favorable safety and efficacy profiles, with particular effectiveness against Gram-positive bacteria. Brilacidin’s ability to modulate pro-inflammatory cytokines and its stability under physiological conditions have positioned it as a potential dualpurpose therapeutic agent, combining antimicrobial action with tissue protection.

Table 2: Ongoing clinical trials and preliminary results for cationic antimicrobial peptides.