LL-37 is a real human peptide with real biology and one disappointing phase IIb trial. It kills microbes and modulates inflammation, and that second property cuts both ways: it drives disease in psoriasis and rosacea. Antimicrobial peptides as a class are proven drugs, but only three are FDA-approved, and most new candidates have failed.
Key points
- LL-37 is the only human cathelicidin: a 37-residue helical peptide with broad-spectrum antimicrobial and immunomodulatory activity [1].
- Toll-like receptor activation in human macrophages induces cathelicidin through a vitamin D-dependent pathway [2].
- In venous ulcers, topical LL-37 was associated with better healing in the first-in-human trial (34 patients), but the 148-patient phase IIb showed no difference from placebo in the full population [3][4].
- An estimated 4.71 million deaths were associated with bacterial resistance in 2021, and the 2050 forecast places Latin America and the Caribbean among the regions with the highest mortality [8].
- Of more than 3000 antimicrobial peptides described, only gramicidin, daptomycin and colistin have been approved by the FDA. Structural and functional limitations, together with a stricter regulatory environment, have hampered their translation to the clinic [9][16].
US status (October 2026): See the peptide status tracker.
LL-37 is the only human cathelicidin
Antimicrobial peptides are part of the innate immunity of almost every organism. In mammals, one of their main families is the cathelicidins, and humans have a single member: LL-37, an amphipathic, helical 37-residue peptide [1]. It is expressed in skin, the respiratory tract, the gut and the testis, and in neutrophils, monocytes, T cells, B cells and NK cells [1].
Its role goes beyond killing microbes. LL-37 has been described to neutralize lipopolysaccharide, regulate the inflammatory response, recruit adaptive immune cells to the site of infection and promote re-epithelialization and wound closure [1]. That dual nature, antimicrobial and immunomodulatory, explains both its therapeutic promise and its unwanted effects.
Vitamin D switches on cathelicidin in macrophages
In 2006 a study in Science showed that Toll-like receptor activation in human macrophages up-regulated the vitamin D receptor and 1-hydroxylase, which induced cathelicidin and killing of intracellular Mycobacterium tuberculosis [2]. The authors also observed that serum from African-American individuals, with low 25-hydroxyvitamin D, was inefficient at supporting cathelicidin mRNA induction [2].
The finding gave a mechanistic basis to an old observation about vitamin D and tuberculosis. Read it precisely. It demonstrates a biological pathway in cells. It does not show that vitamin D supplementation prevents infections in clinical practice [2].
- 4.71 million: deaths associated with bacterial resistance in 2021 [8]
- 3 of more than 3000: antimicrobial peptides FDA-approved vs those described [9]
- 56%: patients with kidney alterations on murepavadin, where 25 to 40% was expected [15]
In venous ulcers, early promise did not hold in phase IIb
The first-in-human trial enrolled 34 patients with hard-to-heal venous ulcers, treated twice weekly for 4 weeks with topical LL-37 (0.5, 1.6 or 3.2 mg/mL) or placebo [3]. With 0.5 and 1.6 mg/mL, the healing rate constant was about six and three times higher than with placebo (p = 0.003 and p = 0.088; the latter not statistically significant), and mean ulcer area fell 68% and 50% [3]. The highest dose did not differ from placebo, and there were no local or systemic safety concerns [3].
The phase IIb, with 148 patients, was more sobering. In the full population there was no significant improvement in healing with LL-37 vs placebo [4]. A post hoc analysis suggested benefit in large ulcers (at least 10 cm²), which the authors consider grounds for an adequately powered study in that subgroup [4]. The drug was well tolerated at both strengths [4].
One point favors topical development. Although LL-37 is degraded by trypsin and by Pseudomonas aeruginosa elastase, ex vivo, in fluid from chronic venous ulcers, it was fairly resistant to proteolysis for up to 24 hours [5].
The same peptide drives psoriasis and rosacea
The peptide that defends can also perpetuate inflammation. In psoriasis, LL-37 binds self-DNA and turns it into a potent trigger for plasmacytoid dendritic cells, which produce interferon through TLR9. The authors propose that this pathway breaks tolerance to self-DNA [6].
In rosacea, affected people express abnormally high cathelicidin levels in facial skin, with processed forms that differ from those in normal skin, linked to increased stratum corneum tryptic enzyme. In mice, those fragments reproduce the inflammation [7]. The clinical lesson is direct: more LL-37 is not always better.
Antimicrobial resistance is the reason the field matters
The Global Burden of Disease analysis estimated 4.71 million deaths associated with bacterial resistance in 2021, of which 1.14 million were directly attributable to it [8]. The 2050 forecast is 1.91 million attributable and 8.22 million associated deaths, and south Asia and Latin America and the Caribbean are forecast to be the super-regions with the highest resistance mortality rate in 2050 [8]. Deaths associated with carbapenem resistance rose from 619,000 in 1990 to 1.03 million in 2021 [8].
Three antimicrobial peptides are already approved
Of more than 3000 membrane-active antimicrobial peptides described, the FDA has approved three for therapeutic use: gramicidin, daptomycin and colistin [9]. Daptomycin, a last-line lipopeptide against Gram-positive bacteria, forms a complex with calcium and phosphatidylglycerol in the bacterial membrane and depolarizes it [9]. Polymyxins such as colistin have re-emerged as last-resort antibiotics against multidrug-resistant Gram-negative bacteria [10].
Vancomycin is often mentioned alongside them. It is a glycopeptide with a different mechanism: it binds the D-Ala-D-Ala region of lipid II and interferes with peptidoglycan maturation [11]. The approved drugs show the price of the class. In a meta-analysis of 48 studies, pooled polymyxin nephrotoxicity was 45% (48% with colistin and 38% with polymyxin B) [10], and gramicidin S was historically limited to topical use because of hemolytic toxicity [12].
Pexiganan and murepavadin show why so few make it
Pexiganan, a magainin analogue, was tested as a cream in mildly infected diabetic foot ulcers. In two trials with 835 patients, the combined data showed results equivalent to oral ofloxacin, with 85 to 90% clinical improvement, although one of the two trials failed to show equivalence. No significant resistance to pexiganan emerged [13]. Years later, the phase 3 OneStep-1 and OneStep-2 trials, with 389 patients, did not show superiority over vehicle plus standard wound care, nor any difference in ulcer closure [14].
Murepavadin, a peptidomimetic targeting Pseudomonas aeruginosa, reached phase 3 in nosocomial pneumonia. In May 2019 enrollment was temporarily halted because 56% of patients treated in the PRISM-MDR study developed kidney alterations, when 25 to 40% was expected based on the literature and the comparator arm [15].
A review in Lancet Infectious Diseases sums up the balance. Antimicrobial peptides have clear advantages, such as slower emergence of resistance, antibiofilm activity and favorable modulation of the host response. Their structural and functional limitations, together with a stricter regulatory environment, have hampered their translation to the clinic [16].
The limits of the evidence
- The effect of LL-37 in venous ulcers was not confirmed in the full phase IIb population, and the benefit in large ulcers comes from a post hoc analysis [4].
- The vitamin D link was shown in cells, not in clinical prevention trials [2].
- LL-37’s pro-inflammatory role in psoriasis and rosacea indicates that boosting its activity could carry costs [6][7].
What is demonstrated
Antimicrobial peptides are a real drug class, with three FDA-approved members. Daptomycin and colistin are last-resort antibiotics [9][10]. Topical LL-37 was safe and well tolerated in two controlled trials [3][4], and in the pexiganan trial no significant resistance to the peptide emerged, unlike the comparator antibiotic [13]. With resistance mortality rising [8], the class retains recognized advantages, such as slower emergence of resistance and antibiofilm activity, that justify further development [16].
What this means for you
LL-37 has no approved product, and the controlled trials were topical, in venous ulcers. If a patient brings you an injectable LL-37 vial sold online, the trial record does not cover it; research-use-only peptides explains why that channel is not a lawful source, and peptide supplier diligence covers what to check before any peptide reaches a patient. Patients with rosacea or psoriasis are the group where the biology argues hardest against boosting it [6][7].
References
- Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006;1758(9):1408-25. PMID 16716248. Link
- Liu PT, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770-3. PMID 16497887. Link
- Grönberg A, et al. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen. 2014;22(5):613-21. PMID 25041740. Link
- Mahlapuu M, et al. Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: a multicentric prospective randomized placebo-controlled clinical trial. Wound Repair Regen. 2021;29(6):938-950. PMID 34687253. Link
- Grönberg A, et al. Stability of the cathelicidin peptide LL-37 in a non-healing wound environment. Acta Derm Venereol. 2011;91(5):511-5. PMID 21547341. Link
- Lande R, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564-9. PMID 17873860. Link
- Yamasaki K, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975-80. PMID 17676051. Link
- GBD 2021 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. Lancet. 2024;404(10459):1199-1226. PMID 39299261. Link
- Huang HW. DAPTOMYCIN, its membrane-active mechanism vs. that of other antimicrobial peptides. Biochim Biophys Acta Biomembr. 2020;1862(10):183395. PMID 32526177. Link
- Sisay M, et al. Polymyxin-induced nephrotoxicity and its predictors: a systematic review and meta-analysis of studies conducted using RIFLE criteria of acute kidney injury. Pharmacol Res. 2021;163:105328. PMID 33276108. Link
- Stogios PJ, Savchenko A. Molecular mechanisms of vancomycin resistance. Protein Sci. 2020;29(3):654-669. PMID 31899563. Link
- Kalyvas JT, et al. Machine-learning approach to increase the potency and overcome the hemolytic toxicity of gramicidin S. J Med Chem. 2025;68(15):16093-16102. PMID 40694383. Link
- Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis. 2008;47(12):1537-45. PMID 18990064. Link
- Genetic Engineering & Biotechnology News. Dipexium’s diabetic foot ulcer candidate fails phase III trials. October 25, 2016. Link
- Polyphor. Polyphor temporarily halts enrollment in the phase III studies of murepavadin for the treatment of patients with nosocomial pneumonia (press release via BioSpace). May 2019. Link
- Magana M, et al. The value of antimicrobial peptides in the age of resistance. Lancet Infect Dis. 2020;20(9):e216-e230. PMID 32653070. Link
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