Antimicrobial Peptides for Wound Care: Clinical Outlook

Antibiotic resistance is no longer a future problem. It is a present one. The WHO has called it one of the top ten global public health threats, and wound infections sit squarely at the intersection of this crisis. Chronic wounds — diabetic foot ulcers, pressure injuries, venous leg ulcers, surgical site infections — affect an estimated 8.2 million Americans and cost the healthcare system over $28 billion annually. Many of these wounds harbor bacteria that shrug off conventional antibiotics.

Antimicrobial peptides (AMPs) offer a fundamentally different approach. Rather than targeting a single bacterial enzyme or metabolic pathway — the way most antibiotics work — AMPs attack bacterial membranes directly, making resistance far harder to develop. But they do more than kill bacteria. AMPs also recruit immune cells, modulate inflammation, and promote tissue repair. This dual role — antimicrobial and wound-healing — is why they have attracted intense research attention over the past two decades.

Over 3,200 AMPs have been discovered from organisms ranging from frogs to humans. Several have reached clinical trials. The results have been mixed — encouraging efficacy in some cases, disappointing outcomes in others. This article examines where the field stands, which AMPs are closest to clinical use, and what challenges remain between the laboratory and the patient's bedside.

What Are Antimicrobial Peptides?
Why AMPs Matter for Wound Care
How AMPs Kill Bacteria
AMPs Beyond Killing: Immune Modulation and Healing
AMPs in Clinical Development
Comparison to Traditional Antibiotics
Challenges Facing AMP Development
Future Directions
Frequently Asked Questions
The Bottom Line
References

What Are Antimicrobial Peptides?

Antimicrobial peptides are short chains of amino acids — typically 12 to 50 residues — that function as part of the innate immune system in virtually every living organism. Humans produce several families of AMPs, including cathelicidins (such as LL-37) and defensins (alpha-defensins and beta-defensins). These peptides are produced by skin cells, neutrophils, macrophages, and epithelial cells as a first line of defense against invading pathogens.

Most AMPs share a common structural feature: they are amphipathic. One side of the molecule is hydrophobic (fat-loving), the other hydrophilic (water-loving). This allows them to insert into and disrupt bacterial membranes — a mechanism that has remained effective for hundreds of millions of years of evolution.

The term "host defense peptides" is increasingly used instead of "antimicrobial peptides" because it captures their broader biological roles: not just killing pathogens, but also recruiting immune cells, modulating inflammation, and directly promoting wound healing.

Why AMPs Matter for Wound Care

Three converging trends make AMPs particularly relevant for wound management:

The antibiotic resistance crisis. MRSA (methicillin-resistant Staphylococcus aureus), VRE (vancomycin-resistant enterococci), multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae are increasingly common in chronic wounds. The CDC estimates that antibiotic-resistant infections kill over 35,000 Americans annually, and wound infections account for a substantial share.

Chronic wound burden. Approximately 1–2% of the population in developed countries will experience a chronic wound during their lifetime. Diabetic foot ulcers alone affect 15% of diabetic patients, and about 14–24% of those cases lead to amputation. The global wound care market exceeds $20 billion and continues to grow.

Biofilm formation. An estimated 60–80% of chronic wounds contain biofilms — structured microbial communities encased in a protective matrix that makes them up to 1,000 times more resistant to antibiotics than free-floating bacteria. AMPs have shown the ability to disrupt biofilms in ways that conventional antibiotics cannot.

The convergence of these factors has created urgent demand for new antimicrobial approaches — and AMPs, with their membrane-disrupting mechanism and immune-modulating properties, are among the most promising candidates.

How AMPs Kill Bacteria

AMPs use several mechanisms to destroy bacteria, and most can employ multiple mechanisms simultaneously. This is a key advantage over conventional antibiotics, which typically have a single target:

Membrane disruption. The primary mechanism. AMPs bind to the negatively charged bacterial membrane through electrostatic attraction, then insert into the lipid bilayer and form pores. Three pore-formation models have been described: the barrel-stave model (peptides insert vertically, like staves of a barrel), the toroidal pore model (peptides and lipids curve together to form a hole), and the carpet model (peptides accumulate on the surface until a critical concentration causes membrane collapse). The result is the same: loss of membrane integrity, leakage of cellular contents, and bacterial death.

Intracellular targets. Some AMPs cross the membrane without destroying it and attack internal targets — inhibiting DNA or RNA synthesis, blocking protein production, or disrupting metabolic enzymes.

Biofilm disruption. Certain AMPs can penetrate the extracellular polymeric substance (EPS) matrix that protects biofilm-dwelling bacteria, killing cells within the biofilm and disrupting its structure.

Why is resistance so difficult to develop? Because bacterial membranes are fundamental to cell survival. A bacterium cannot easily change the basic structure of its membrane without compromising essential functions. This contrasts sharply with conventional antibiotics, where a single point mutation in a target enzyme can confer resistance. Bacteria do develop some AMP resistance mechanisms (modifying membrane charge, producing proteases that degrade peptides), but these typically come with significant fitness costs.

AMPs Beyond Killing: Immune Modulation and Healing

What distinguishes AMPs from conventional antibiotics for wound care is their dual role. A 2025 review in the International Journal of Molecular Sciences detailed how AMPs bridge innate and adaptive immunity during wound healing, functioning simultaneously as antimicrobial agents and immune modulators (IJMS, 2025).

Immune cell recruitment. AMPs act as chemotactic signals, drawing neutrophils, macrophages, and dendritic cells to wound sites. LL-37, for example, recruits and activates T cells and modulates B cell function, connecting the initial innate response to longer-term adaptive immunity.

Macrophage polarization. AMPs promote polarization of macrophages toward the M2 (reparative) phenotype, which is associated with tissue regeneration rather than ongoing inflammation. This shift is a key step in moving chronic wounds from the inflammatory phase into the proliferative healing phase.

Cytokine modulation. AMPs regulate the production of pro-inflammatory cytokines (TNF-alpha, IL-6) and anti-inflammatory cytokines (IL-10), helping to resolve the persistent inflammation that stalls chronic wound healing.

Direct wound healing effects. Specific AMPs promote keratinocyte migration, fibroblast proliferation, angiogenesis, and extracellular matrix deposition. LL-37 activates the epidermal growth factor receptor (EGFR) and its downstream ERK1/2 signaling pathway, directly stimulating the re-epithelialization that closes wounds.

Angiogenesis. Human beta-defensin-3 (hBD-3) induces angiogenesis — the formation of new blood vessels that supply oxygen and nutrients to healing tissue. This is mediated through EGFR, Src, JNK, p38, and NF-kB signaling pathways.

This combination of antimicrobial and healing activity means an AMP wound treatment could theoretically clear infection and accelerate repair in a single agent — something no conventional antibiotic can do.

AMPs in Clinical Development

LL-37 (Cathelicidin): Human Innate Defense

What it is: LL-37 is the only cathelicidin expressed in humans. It is a 37-amino-acid peptide cleaved from its precursor protein hCAP-18 (human cationic antimicrobial protein). It is produced by neutrophils, macrophages, keratinocytes, and epithelial cells — the cells most active at wound sites.

Antimicrobial activity: LL-37 has broad-spectrum activity against Gram-positive and Gram-negative bacteria, fungi, and some viruses. It is particularly effective against wound pathogens including S. aureus, P. aeruginosa, and E. coli. LL-37-derived peptides have been shown to eradicate multidrug-resistant S. aureus from thermally wounded human skin equivalents.

Wound healing mechanisms: LL-37 promotes re-epithelialization by activating EGFR and ERK1/2 signaling. It upregulates VEGF-A and TGF-beta, accelerating blood vessel formation and granulation tissue development. It downregulates IL-6 and TNF-alpha, resolving chronic inflammation. Research shows LL-37 protects against inflammatory damage by preventing the activation of enzymes and regulators involved in inflammatory responses (Journal of Translational Medicine, 2022).

Clinical trial results:

Phase I/II (venous leg ulcers): A first-in-human randomized, double-blind trial tested synthetic LL-37 (0.5, 1.6, or 3.2 mg/mL) versus placebo applied twice weekly to hard-to-heal venous leg ulcers in 34 patients. The healing rate constants for the 0.5 mg/mL and 1.6 mg/mL doses were approximately six-fold and three-fold higher than placebo, respectively (p = 0.003 and p = 0.088). The treatment was safe and well tolerated (Grönberg et al., 2014).
Phase IIb HEAL LL-37 trial: A larger study of 148 patients with hard-to-heal venous leg ulcers. The primary efficacy analysis on the full population did not show significant improvement over placebo. However, a post hoc analysis revealed statistically significant improvement in patients with large wounds (10 cm² or greater at baseline). The drug was safe in both dose strengths tested (PMC, 2022).
Oncology application: An LL-37-derived peptide that induces antitumor effects in melanoma patients completed Phase I/II trials in 2024, demonstrating that LL-37-based therapeutics can reach advanced clinical stages.

Status: Not FDA-approved. Clinical development continues. The Phase IIb results suggest that patient selection (wound size, chronicity) may be important for demonstrating efficacy. For deeper coverage of LL-37 research, see our comprehensive LL-37 research overview and the comparison with thymosin alpha-1.

Pexiganan (MSI-78): The Magainin Analog

What it is: Pexiganan is a 22-amino-acid synthetic analog of magainin-2, originally isolated from the skin of the African clawed frog (Xenopus laevis). It was developed as a topical cream (Locilex) for treating infected diabetic foot ulcers.

Antimicrobial activity: Broad-spectrum activity against Gram-positive and Gram-negative aerobes and anaerobes. MIC90 values of 16 mcg/mL or less for common wound pathogens including S. aureus, coagulase-negative staphylococci, and P. aeruginosa. It does not exhibit cross-resistance with beta-lactams, quinolones, macrolides, or lincosamides — meaning it can still kill bacteria that have become resistant to multiple conventional antibiotics.

Clinical trial history:

Phase III trials evaluated pexiganan 0.8% cream for mild infections in diabetic foot ulcers (NCT01590758, NCT01594762). These trials enrolled approximately 1,000 patients total.
Results demonstrated the safety of pexiganan but failed to show consistent superiority over the comparator (ofloxacin). The FDA did not approve the drug, citing insufficient evidence of efficacy.
Analysis suggests that AMP dosing, formulation optimization, and selected clinical endpoints likely contributed to the lack of demonstrated clinical success.

Why it matters despite "failure": Pexiganan's Phase III experience illustrates a broader challenge for AMPs in wound care. The peptide works against the target bacteria in vitro. But the transition from test tube to complex wound environment — where proteases degrade peptides, wound fluid dilutes concentrations, and biofilms create barriers — introduces variables that laboratory testing does not capture. The lesson from pexiganan is not that AMPs do not work, but that formulation and delivery matter as much as antimicrobial potency.

Status: Development continues with plans for additional trials in complicated skin and soft tissue infections, burns, and pressure ulcers. Reformulation efforts aim to address the delivery challenges identified in earlier trials.

Omiganan (CLS001): The Indolicidin Derivative

What it is: Omiganan is a 12-amino-acid analog of indolicidin, an AMP isolated from bovine neutrophils. It has been tested across multiple dermatological applications.

Clinical trials:

Catheter infections: Showed efficacy in preventing catheter-related infections but failed to demonstrate advantage over existing therapies in Phase III (NCT00231153).
Atopic dermatitis: A Phase II randomized controlled trial showed omiganan 2.5% recovered cutaneous dysbiosis by reducing Staphylococcus species abundance and increasing microbial diversity. However, this microbiome improvement did not translate into clinical symptom improvement, suggesting that selectively targeting the microbiome alone is not sufficient to treat the disease (Lancet, 2020).
Rosacea and acne: Additional trials explored omiganan for papulopustular rosacea and acne vulgaris (NCT02576847, NCT02571998).
Genital warts: Tested as a topical treatment (NCT02849262).

Key insight: The atopic dermatitis results carry an important lesson for the AMP field. Correcting microbial imbalance without simultaneously addressing the host inflammatory response may not be enough for clinical improvement. This supports the growing view that effective AMP wound therapies will need to leverage both the antimicrobial and immune-modulating properties of these peptides.

Brilacidin (PMX-30063): The Defensin Mimetic

What it is: Brilacidin is not a peptide in the traditional sense. It is a non-peptide small molecule designed to mimic the structure and function of defensins — the family of AMPs that form a key part of human innate immunity. This makes it a "host defense protein mimetic" or "defensin mimetic."

Why mimetics matter: Natural peptides face stability challenges — they are degraded by proteases, have short half-lives, and can be expensive to manufacture. By designing a small molecule that replicates a defensin's membrane-disrupting function without using a peptide backbone, brilacidin overcomes several of these limitations.

Clinical trials:

Phase 2b for ABSSSI (acute bacterial skin and skin structure infection): A single intravenous dose of brilacidin showed comparable safety and efficacy to a 7-day regimen of FDA-approved daptomycin. This is a remarkable result — matching a full week of conventional antibiotic therapy with a single dose of a novel mechanism.
Four completed clinical trials total: NCT02324335, NCT02052388, and NCT01211470 at Phase 2, plus NCT04240223 at Phase 1.
COVID-19 application: A 2022 study showed brilacidin inhibited SARS-CoV-2 infection by blocking viral entry, demonstrating the broad-spectrum potential of defensin mimetics beyond bacterial infections (PMC, 2022).

Status: Brilacidin represents what may be the most practical path for AMP-based wound therapeutics — overcoming the stability and cost challenges of peptides while retaining their mechanism of action.

Murepavadin: Targeting Pseudomonas

What it is: Murepavadin is a peptidomimetic antibiotic that specifically targets Pseudomonas aeruginosa — one of the most problematic wound pathogens, notorious for biofilm formation and multidrug resistance.

Why it matters: Unlike the broad-spectrum AMPs above, murepavadin has a targeted mechanism: it blocks the lipopolysaccharide transport protein LptD, which is essential for outer membrane assembly in Pseudomonas. This gives it specificity without the toxicity concerns that can come with broad membrane disruption.

Clinical status: Murepavadin has passed Phase III clinical trials. Its dual mechanism — biofilm disruption combined with rapid bactericidal activity — is significantly more effective against Pseudomonas than traditional antibiotics. This makes it the most clinically advanced AMP-type agent in the pipeline, though its narrow spectrum limits applicability to Pseudomonas-specific infections.

Comparison to Traditional Antibiotics

Feature	Conventional Antibiotics	Antimicrobial Peptides
Mechanism	Single target (enzyme, ribosome, cell wall synthesis)	Multiple mechanisms (membrane disruption + intracellular targets)
Resistance development	Rapid (single mutation can confer resistance)	Slow (membrane restructuring costly to bacteria)
Spectrum	Variable (narrow to broad)	Generally broad
Biofilm activity	Poor (most cannot penetrate biofilm matrix)	Moderate to good (several AMPs disrupt biofilms)
Wound healing effects	None (some impair healing)	Direct pro-healing activity (immune modulation, angiogenesis, re-epithelialization)
Stability in wounds	Generally stable	Variable (many degraded by wound proteases)
Cost	Low (generics available)	High (complex synthesis)
Resistance risk to host cells	Low	Moderate (some AMPs show cytotoxicity at high doses)

The comparison highlights both the promise and the challenge. AMPs offer mechanistic advantages that antibiotics cannot match — particularly the combination of antimicrobial and wound-healing activity. But stability, cost, and cytotoxicity concerns have slowed clinical translation.

Challenges Facing AMP Development

Cytotoxicity. The same membrane-disrupting mechanism that kills bacteria can also damage human cells at higher concentrations. The therapeutic window — the gap between the dose that kills bacteria and the dose that harms human tissue — is narrower for many AMPs than for conventional antibiotics. LL-37, for example, can trigger inflammation at high concentrations.

Protease degradation. Wound fluid is rich in proteases that rapidly break down peptides. This reduces effective concentrations at the wound site and necessitates either frequent reapplication or advanced delivery systems that protect the peptide from degradation.

Serum binding and inactivation. Blood components, particularly serum proteins and salts, can reduce AMP activity. This means that in vitro potency does not always predict in vivo effectiveness — a factor that likely contributed to pexiganan's Phase III disappointment.

Manufacturing costs. Synthetic peptide production is more expensive than small-molecule antibiotic manufacturing. Solid-phase peptide synthesis for clinical-grade AMPs can cost 10–100 times more per gram than conventional antibiotics. This cost barrier limits commercial viability, especially for wound care products that compete with generic antibiotics.

Clinical trial design. Wound healing trials are inherently complex. Wounds vary in size, depth, location, chronicity, underlying cause, and microbial colonization. Designing trials that control for these variables while demonstrating clear efficacy is a challenge that has tripped up several AMP candidates.

Regulatory pathway. AMPs with dual antimicrobial and wound-healing activity do not fit neatly into existing regulatory categories. Are they antibiotics? Wound-healing agents? Both? The regulatory pathway affects trial design, approval requirements, and commercial classification.

Future Directions

Despite the challenges, several approaches are converging to solve the problems that have limited AMP clinical success:

Smart biomaterial integration. Researchers are embedding AMPs into wound dressings, hydrogels, and nanofiber scaffolds that provide sustained, controlled release at the wound site. This addresses both the protease degradation and the dosing frequency problems. A 2025 review in Frontiers in Bioengineering and Biotechnology documented polypeptide-based self-assembled matrices specifically designed for wound healing applications (Frontiers, 2025).

Peptide engineering. Modifications like D-amino acid substitution (which makes peptides invisible to proteases), cyclization (which improves stability), and lipidation (which increases membrane affinity) are producing next-generation AMPs with improved pharmacological profiles. Learn more about these approaches in our guide to peptide modifications.

Defensin mimetics. Brilacidin's clinical success demonstrates that non-peptide small molecules can replicate AMP function without the stability and cost limitations of peptides. This approach may ultimately prove more commercially viable than natural peptide development.

Combination strategies. Using AMPs alongside conventional antibiotics may produce synergistic effects — the AMP disrupts the bacterial membrane, making it easier for the antibiotic to reach its intracellular target. This could lower effective doses of both agents, reducing toxicity and cost.

AI-driven peptide design. Machine learning algorithms are now being used to design novel AMP sequences optimized for specific properties — antimicrobial potency, selectivity for bacterial over human membranes, stability, and manufacturing feasibility. A 2025 study in ACS Nano demonstrated how machine learning can accelerate peptide nanomaterial discovery, a principle directly applicable to AMP optimization.

Topical formulation advances. New formulation strategies — including liposomal encapsulation, microemulsions, and stimuli-responsive gels that release AMPs in response to wound pH or bacterial enzyme activity — aim to solve the delivery problem that has limited earlier clinical candidates.

Frequently Asked Questions

Are any antimicrobial peptides FDA-approved for wound care? No AMP is currently FDA-approved specifically for wound treatment. Murepavadin (targeting Pseudomonas) has completed Phase III trials and is the furthest along the regulatory pathway. Brilacidin showed single-dose efficacy comparable to 7-day daptomycin in skin infections but has not yet received approval. LL-37 has completed Phase II trials for venous leg ulcers with mixed but encouraging results.

How do AMPs compare to silver-based wound dressings? Silver dressings work through a different mechanism — releasing silver ions that are toxic to bacteria. Like AMPs, silver has broad-spectrum antimicrobial activity and low resistance rates. However, silver does not promote wound healing and can be cytotoxic to fibroblasts and keratinocytes at higher concentrations. AMPs have the theoretical advantage of combining antimicrobial and pro-healing effects in a single agent.

Can bacteria become resistant to antimicrobial peptides? Yes, but it is much harder than developing resistance to conventional antibiotics. Bacteria can modify their membrane charge, produce proteases that degrade peptides, or use efflux pumps to expel AMPs. However, these resistance mechanisms typically come with significant fitness costs — the bacteria become less competitive in the absence of AMP pressure. The millions of years that AMPs have remained effective in nature suggests that clinically meaningful resistance is unlikely to develop rapidly.

What about using the body's own AMPs to treat wounds? This is an active area of research. Strategies include applying vitamin D (which upregulates LL-37 production in skin cells), using probiotics that stimulate AMP expression, and developing gene therapies that increase local AMP production at wound sites. These approaches could complement direct AMP application. For more on the body's natural antimicrobial defenses, see our guide to antimicrobial peptides as natural defense molecules.

Why have several AMP clinical trials failed? The pattern of in vitro success but clinical disappointment has several explanations: wound environments are more complex than lab conditions (proteases, serum proteins, biofilms); clinical trial endpoints may not capture the full benefit of AMPs (which include immune modulation and healing, not just bacterial killing); formulations have not always delivered adequate peptide concentrations to wound sites; and patient populations in chronic wound trials are highly heterogeneous, making it difficult to demonstrate statistically significant effects.

The Bottom Line

Antimicrobial peptides represent one of the most scientifically compelling alternatives to conventional antibiotics for wound care. Their dual role — killing pathogens while simultaneously promoting immune defense and tissue repair — addresses a gap that no existing wound treatment fills.

The clinical results so far are a mixed picture. LL-37 showed meaningful wound healing acceleration in its Phase I/II trial but missed its primary endpoint in a larger Phase IIb study (with a subgroup showing benefit). Pexiganan proved safe but not sufficiently effective against its comparator. Brilacidin matched a week of daptomycin therapy with a single dose. Murepavadin has reached Phase III for Pseudomonas infections.

The path forward likely lies not in using natural AMPs as-is, but in the next generation of approaches: engineered peptides with improved stability, defensin mimetics that overcome the cost and degradation barriers, smart biomaterial delivery systems, and combination therapies that leverage AMP-antibiotic synergy. For patients with chronic or antibiotic-resistant wound infections, these developments cannot come soon enough.

References

AMPs in wound healing and skin regeneration: dual roles in immunity and microbial defense (2025). International Journal of Molecular Sciences, 26(13), 5920. MDPI
Antimicrobial peptide biological activity, delivery systems and clinical translation status and challenges (2025). Journal of Translational Medicine. Springer
Antimicrobial peptides: from discovery to developmental applications (2025). Applied and Environmental Microbiology. ASM
Grönberg, A., et al. (2014). Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers. Wound Repair and Regeneration, 22(5), 613–621. PubMed
Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: a multicentric prospective randomized placebo-controlled clinical trial (2022). Wound Repair and Regeneration. PMC
Therapeutic potential of antimicrobial peptides for treatment of wound infection (2022). American Journal of Physiology — Cell Physiology. APS
Lázár, V., et al. (2022). Brilacidin, a non-peptide defensin-mimetic molecule, inhibits SARS-CoV-2 infection by blocking viral entry. Frontiers in Immunology, 13. PMC
Design and applications of self-assembled polypeptide matrices in wound healing (2025). Frontiers in Bioengineering and Biotechnology. Frontiers
Antimicrobial peptides: a promising frontier to combat antibiotic resistant pathogens (2025). Microbial Cell Factories. PMC
Topical antimicrobial peptide omiganan recovers cutaneous dysbiosis but does not improve clinical symptoms in patients with atopic dermatitis (2020). Journal of the American Academy of Dermatology. PubMed

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