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LL-37 Antimicrobial Research: Laboratory to Clinic

LL-37 is the only cathelicidin antimicrobial peptide produced in the human body. It kills bacteria, disrupts biofilms, fights viruses, and shapes your immune response — all at the same time. For two decades, researchers have been trying to turn this natural defense molecule into a usable drug.

LL-37 is the only cathelicidin antimicrobial peptide produced in the human body. It kills bacteria, disrupts biofilms, fights viruses, and shapes your immune response — all at the same time. For two decades, researchers have been trying to turn this natural defense molecule into a usable drug. Here is what the science actually shows.

Table of Contents

What Is LL-37?

LL-37 is a 37-amino-acid peptide released from a larger precursor protein called hCAP-18. Your neutrophils store it in their granules. Epithelial cells in your skin, lungs, and gut lining produce it. It shows up in plasma, breast milk, sweat, saliva, and airway fluid [1].

The gene that codes for it — CAMP, located on chromosome 3p21.3 — is regulated by vitamin D. When your body's active vitamin D levels rise, CAMP expression increases, and you produce more LL-37 [2]. This connection between vitamin D status and antimicrobial defense has become an active area of research on its own.

What makes LL-37 unusual among antimicrobial peptides is its range. It does not just punch holes in bacterial membranes. It also neutralizes bacterial toxins, breaks apart biofilms, kills viruses through multiple mechanisms, recruits immune cells, and modulates inflammation. That versatility is exactly what makes it interesting as a drug candidate — and what makes it difficult to develop into one.

Antibacterial Activity: What the Lab Studies Found

LL-37 has demonstrated activity against more than 38 bacterial species, 16 fungi, and 16 viruses in laboratory testing [1]. Its primary mechanism involves electrostatic attraction to negatively charged bacterial membranes, followed by membrane disruption and cell death.

Gram-Negative Bacteria

A 2024 study published in mSphere tested LL-37 against non-growing Escherichia coli — the dormant, hard-to-kill bacteria that often survive antibiotic treatment. The peptide remained effective against these metabolically inactive cells, though it worked more slowly than against actively dividing bacteria [3]. This finding matters because dormant bacteria are a major driver of persistent and recurring infections.

Gram-Positive Bacteria (Including MRSA)

Against Staphylococcus aureus, including methicillin-resistant strains (MRSA), the story is more nuanced. A study using MRSA strains isolated from chronic wound infections found minimum inhibitory concentration (MIC) values of 132.3 mg/L for MRSA, compared to 89.6 mg/L for methicillin-susceptible strains [4]. Those are relatively high concentrations — higher than what the body naturally produces at most tissue sites.

But the MIC numbers do not tell the full story. At concentrations well below the MIC, LL-37 still affected quorum sensing genes (agrA, RNAIII, atlA) that bacteria use to coordinate biofilm formation and virulence [4]. This sublethal activity may be as clinically relevant as outright bacterial killing.

Synergy With Antibiotics

LL-37's membrane-disrupting activity creates openings for conventional antibiotics. Two truncated LL-37 fragments — LL-13 and LL-17 — showed synergy with vancomycin against both MRSA and vancomycin-resistant S. aureus (VRSA) strains. Pretreatment with these fragments restored vancomycin sensitivity in resistant strains [5]. Similarly, fragments FK16 and FK13 improved the performance of penicillin G and ampicillin against MRSA [6].

The mechanism is straightforward: by permeabilizing the bacterial membrane, these peptides let antibiotics reach their intracellular targets more easily.

Biofilm Disruption Research

Biofilms — structured bacterial communities encased in a protective matrix — are responsible for roughly 80% of chronic infections. They resist antibiotics at concentrations 100 to 1,000 times higher than needed to kill free-floating bacteria. LL-37's ability to disrupt biofilms may be its most clinically relevant property.

StudyTarget OrganismKey Finding
Kang et al. (2019)S. aureusLL-37 bactericidal against 24h and 48h mature biofilms [7]
Singh et al. (2021)MRSA/MSSA from chronic woundsLL-37 reduced biofilm at sub-MIC concentrations; affected quorum sensing genes [4]
de Breij et al. (2018)MRSA on burn wound skin modelsLL-37 derivative P60.4Ac eradicated MRSA from human skin equivalents [8]
Mohamed et al. (2017)S. aureus on titaniumLL-37 inhibited biofilm on titanium alloy surfaces [7]

The results are not entirely consistent. Some studies report that LL-37 fails to disrupt pre-formed biofilms, while others show dose-dependent clearance of mature biofilms [7]. The discrepancy likely comes down to experimental conditions — the bacterial strain, biofilm age, growth medium, and LL-37 concentration all affect outcomes.

What does seem reliable: LL-37 reduces bacterial attachment to surfaces, interferes with quorum sensing signaling that maintains biofilm architecture, and works better when combined with other agents.

Antiviral Research

LL-37's antiviral activity spans a surprising range of pathogens, and the mechanisms vary by virus type.

Influenza A

In a mouse model, LL-37 and its murine equivalent mCRAMP reduced influenza disease severity and viral replication to levels comparable to the antiviral drug zanamivir [9]. Under electron microscopy, LL-37 appeared to disrupt viral envelopes directly. But unlike other antimicrobial molecules (such as collectins), it did not cause viral aggregation. Instead, it blocked a post-entry step in viral replication — after the virus entered cells but before it began copying its RNA [10].

Treated mice also had lower levels of pro-inflammatory cytokines in their lungs, suggesting LL-37 dampened the destructive immune overreaction that drives severe influenza illness [9].

HIV-1

LL-37 inhibits HIV-1 replication in peripheral blood mononuclear cells in vitro. The mechanism here is entirely different from its action against influenza. Rather than disrupting viral membranes, LL-37 inhibits HIV reverse transcriptase and protease — two enzymes the virus needs to replicate [11]. This does not require direct contact between the peptide and the virus.

SARS-CoV-2

Biophysical studies show that LL-37 can bind to both the SARS-CoV-2 spike protein and the human ACE2 receptor, potentially blocking viral entry. Researchers also observed that LL-37 disrupts the SARS-CoV-2 viral membrane [12]. Clinical observations found an inverse correlation between patients' LL-37 levels and COVID-19 severity — those with higher circulating LL-37 tended to have milder disease [13].

Other Viruses

Laboratory activity has been documented against respiratory syncytial virus (RSV), herpes simplex virus, dengue, Zika, rotavirus, adenovirus, and Venezuelan equine encephalitis virus [1]. Notably, LL-37 can neutralize non-enveloped viruses like adenovirus, meaning its antiviral activity goes beyond simple membrane disruption.

Immunomodulatory Effects

LL-37 does not just kill pathogens directly. It shapes how your immune system responds to them — and this dual role may matter more than its direct antimicrobial effects.

Pro-Inflammatory Actions

  • Stimulates production of IL-8, IL-12p40, and IL-1β from monocytes and epithelial cells [14]
  • Activates the P2X7 receptor on macrophages, triggering inflammasome activation and release of IL-1β and IL-18 [14]
  • Induces type I interferons in plasmacytoid dendritic cells and keratinocytes [14]
  • Triggers mast cell degranulation [14]

Anti-Inflammatory Actions

  • Inhibits AIM2 inflammasome formation [14]
  • Suppresses IFN-γ, TNF-α, and IL-4 production [14]
  • Neutralizes bacterial lipopolysaccharide (LPS), preventing it from triggering excessive inflammation [2]
  • Promotes generation of regulatory T cells (Tregs), which dampen overactive immune responses [15]

This push-and-pull is context-dependent. In the early stages of infection, LL-37 amplifies inflammation to help fight pathogens. As the infection resolves, it shifts toward anti-inflammatory signaling. When this balance breaks down, LL-37 contributes to autoimmune conditions — it has been implicated in the pathogenesis of psoriasis, systemic lupus erythematosus, and rheumatoid arthritis [16].

For those interested in peptides that work with the immune system, our guide on best peptides for immune support covers several compounds that interact with overlapping pathways.

The Wound Healing Clinical Trial

The most important clinical data for LL-37 comes from a Phase I/II randomized, placebo-controlled trial in patients with hard-to-heal venous leg ulcers. Published in Wound Repair and Regeneration in 2014, this first-in-human study tested topical LL-37 (under the drug name ropocamptide) at three doses [17].

Study Design

  • Participants: 34 patients with chronic venous leg ulcers
  • Design: 3-week placebo run-in, followed by 4-week randomized double-blind treatment, then 4-week follow-up
  • Doses tested: 0.5, 1.6, and 3.2 mg/mL topical LL-37, applied twice weekly
  • Sponsor: Promore Pharma (formerly Lipopeptide AB), Solna, Sweden

Results

DoseWound Area ReductionHealing Rate vs. PlaceboStatistical Significance
0.5 mg/mL68%~6-fold fasterp = 0.003
1.6 mg/mL50%~3-fold fasterp = 0.088
3.2 mg/mLNo improvementSimilar to placeboNot significant
Placebo———

The two lower doses markedly outperformed placebo. The highest dose did not. This inverted dose-response pattern — where more is not better — is consistent with the known biology of LL-37. At low concentrations, it promotes keratinocyte migration and angiogenesis. At high concentrations, it can become cytotoxic to human cells [17].

No safety concerns were identified. No local or systemic adverse events differed between treatment groups and placebo.

The biological rationale for wound healing rests on earlier preclinical work showing that LL-37 is naturally present in healthy wound margins but absent from chronic ulcer epithelium [18]. It drives re-epithelialization by activating epidermal growth factor receptor (EGFR) signaling in keratinocytes [19] and stimulates blood vessel formation [20]. You can find more on peptides in this space in our wound healing peptide guide.

LL-37 Derivatives in Clinical Development

Because native LL-37 has stability and cost issues, researchers have developed shorter, modified versions. Here is where they stand.

OP-145 (P60.4Ac) — Chronic Ear Infections

OP-145 is a 24-amino-acid derivative created by removing the proteolytically unstable N-terminal portion of LL-37. It entered Phase II clinical trials for chronic bacterial middle ear infections (chronic otitis media). The peptide showed efficacy in treating patients, but clinical trials were not continued [8, 21]. The reasons for discontinuation have not been publicly disclosed.

SAAP-148 — Next-Generation Derivative

Following OP-145's discontinuation, researchers developed SAAP-148, another 24-amino-acid peptide designed from LL-37 consensus sequences. In preclinical testing, SAAP-148 outperformed every other antimicrobial peptide tested, killing both actively dividing and dormant bacteria, including persister cells within biofilms [8]. It is currently in preclinical development.

LL-37 in Melanoma — Phase I/II

An LL-37-derived peptide was tested via intratumoral injection in melanoma patients in a Phase I/II clinical trial completed in 2024. The approach relies on LL-37's ability to activate plasmacytoid dendritic cells within tumors, triggering an immune-mediated anti-tumor response [1, 22].

Anticancer Research

LL-37's relationship with cancer is complicated. At low concentrations (around 5 μg/mL), it appears to promote tumor growth in ovarian, lung, breast, and prostate cancers, as well as melanoma [23]. At higher concentrations, it kills colon cancer cells, gastric cancer cells, and hematologic malignancies through apoptosis induction [23].

The most promising anticancer data comes from pancreatic cancer research. LL-37 induced DNA damage and cell cycle arrest in pancreatic cancer cells by generating reactive oxygen species. It also suppressed autophagy through mTOR signaling activation, leading to mitochondrial dysfunction and cancer cell death — both in vitro and in animal models [24].

This concentration-dependent, tissue-specific duality makes LL-37 a challenging anticancer candidate. The therapeutic window where it kills cancer without promoting it elsewhere is narrow and not yet well defined.

Challenges and Limitations

Despite two decades of research, LL-37 faces real barriers to clinical use.

Cost of production. Synthesizing a 37-amino-acid peptide at pharmaceutical scale is expensive. Shorter derivatives partially address this, but manufacturing costs remain higher than for small-molecule drugs.

Proteolytic degradation. Enzymes in blood, tissue, and wound fluid break down LL-37 quickly. Its half-life in biological environments is short, which complicates dosing [25]. Researchers are experimenting with PEGylation, cyclization, and nanocarrier delivery systems to extend it.

Cytotoxicity at high concentrations. LL-37 does not discriminate perfectly between bacterial and human membranes. At the concentrations needed to kill some pathogens directly, it damages human cells too [1]. This is why the wound healing trial found no benefit at the highest dose.

Physiological salt sensitivity. LL-37's antimicrobial activity drops significantly in the presence of salt concentrations found in normal body fluids [1]. Activity measured in buffer does not always translate to activity in real tissue environments.

Resistance development. While the initial assumption was that bacteria would struggle to develop resistance to membrane-disrupting peptides, clinical S. aureus strains have shown increased resistance after repeated sublethal LL-37 exposure [4]. The extent and clinical significance of this resistance remain debated.

FAQ

How is LL-37 different from conventional antibiotics? Conventional antibiotics typically target a single bacterial process — cell wall synthesis, protein production, or DNA replication. LL-37 works primarily by disrupting bacterial membranes, which is harder for bacteria to evolve resistance against. It also modulates the host immune response, something antibiotics do not do. However, LL-37 is less potent on a per-dose basis than most antibiotics and is more expensive to produce.

Has LL-37 been approved as a drug anywhere? No. As of early 2026, no LL-37-based drug has received regulatory approval. The wound healing trial (using ropocamptide) showed positive results at lower doses but has not yet advanced to Phase III. The OP-145 derivative reached Phase II for ear infections but was not continued.

Does vitamin D supplementation increase LL-37 levels? Yes. The CAMP gene has a vitamin D response element in its promoter. Multiple studies have shown that vitamin D supplementation increases LL-37 expression in various tissues [2]. Whether this translates to meaningful clinical antimicrobial benefit is still under investigation.

Can LL-37 be combined with antibiotics? Laboratory studies consistently show synergy between LL-37 (or its fragments) and conventional antibiotics like vancomycin, penicillin, and ampicillin. The peptide permeabilizes bacterial membranes, allowing antibiotics better access to intracellular targets [5, 6]. Clinical combination studies have not yet been conducted.

What is the connection between LL-37 and defensins? Both are human antimicrobial peptides that serve as first-line immune defenses. Defensins and LL-37 often work in the same tissues and can have complementary or synergistic effects. They share some immunomodulatory functions but have distinct structures and mechanisms.

The Bottom Line

LL-37 is one of the most thoroughly studied antimicrobial peptides in existence. The research shows real antibacterial activity (especially against biofilms), broad antiviral effects, and meaningful immunomodulatory properties. The wound healing clinical trial demonstrated that topical LL-37 at low doses can accelerate healing of chronic ulcers by three- to six-fold compared to placebo — a striking result.

But turning a natural defense peptide into a drug is hard. Stability, cost, cytotoxicity, and salt sensitivity remain genuine obstacles. The clinical pipeline is thin: one wound healing trial with strong Phase I/II results, a discontinued Phase II trial for ear infections, and early-stage melanoma work.

The most promising near-term path may not be LL-37 itself but its derivatives — shorter, more stable peptides like SAAP-148 that retain the parent molecule's best properties while shedding its worst limitations. For researchers studying peptide stacking and immune-modulating peptides, LL-37 remains a central molecule to understand.

References

  1. Al-Ayed T, et al. LL-37, the master antimicrobial peptide, its multifaceted role from combating infections to cancer immunity. Journal of Antimicrobial Chemotherapy. 2024. PubMed

  2. Vandamme D, et al. A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cellular Immunology. 2012;280(1):22-35.

  3. Matsuzaki K, et al. Antimicrobial peptide LL37 is potent against non-growing Escherichia coli cells despite a slower action rate. mSphere. 2024. mSphere

  4. Singh PK, et al. Efficacy of antimicrobial peptide LL-37 against biofilm forming Staphylococcus aureus strains obtained from chronic wound infections. Microbial Pathogenesis. 2022;162:105368. PubMed

  5. Luo Y, et al. Evaluation of LL-37 antimicrobial peptide derivatives alone and in combination with vancomycin against S. aureus. Journal of Antibiotics. 2019;72:344-352. Nature

  6. Morroni G, et al. LL37-derived fragments improve the antibacterial potential of penicillin G and ampicillin against methicillin-resistant Staphylococcus aureus. Antibiotics. 2023;12(9):1398. MDPI

  7. Kang J, et al. Antimicrobial peptide LL-37 is bactericidal against Staphylococcus aureus biofilms. PLOS ONE. 2019;14(6):e0216676. PLOS ONE

  8. de Breij A, et al. LL-37-derived peptides eradicate multidrug-resistant Staphylococcus aureus from thermally wounded human skin equivalents. Antimicrobial Agents and Chemotherapy. 2018;62(2):e02554-14. ASM

  9. Barlow PG, et al. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLOS ONE. 2011;6(10):e25333. PLOS ONE

  10. Tripathi S, et al. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. Journal of General Virology. 2013;94(1):40-49. PMC

  11. Wong JH, et al. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Peptides. 2011;32(4):752-755.

  12. Zhang L, et al. HD5 and LL-37 inhibit SARS-CoV and SARS-CoV-2 binding to human ACE2 by molecular simulation. Interdisciplinary Sciences. 2021;13:766-777. PMC

  13. Lokhande KB, et al. Niacinamide enhances cathelicidin mediated SARS-CoV-2 membrane disruption. Frontiers in Immunology. 2023;14:1255478. Frontiers

  14. Yang B, et al. Significance of LL-37 on immunomodulation and disease outcome. BioMed Research International. 2020;2020:8349712. PMC

  15. Santos TL, et al. LL-37 treatment on human peripheral blood mononuclear cells modulates immune response and promotes regulatory T-cells generation. Biomedicine & Pharmacotherapy. 2019;108:1584-1590. PubMed

  16. Kahlenberg JM, Kaplan MJ. Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. Rheumatic Disease Clinics of North America. 2013;39(4):735-749. PMC

  17. Gronberg 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 and Regeneration. 2014;22(5):613-621. PubMed

  18. Heilborn JD, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. Journal of Investigative Dermatology. 2003;120(3):379-389. PubMed

  19. Tokumaru S, et al. Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. Journal of Immunology. 2005;175(7):4662-4668. PubMed

  20. Ramos R, et al. Wound healing activity of the human antimicrobial peptide LL37. Peptides. 2011;32(7):1469-1476. PubMed

  21. Malanovic N, Lohner K. Antimicrobial peptides targeting gram-positive bacteria. Pharmaceuticals. 2016;9(3):59. PMC

  22. Felicio MR, et al. Dermatologic toxicity from novel therapy using antimicrobial peptide LL-37 in melanoma. Journal of Cutaneous Pathology. 2018;45(10):801-808. PubMed

  23. Ren SX, et al. The human cathelicidin antimicrobial peptide LL-37 and mimics are potential anticancer drugs. Frontiers in Oncology. 2015;5:144. PMC

  24. Chen X, et al. The human cathelicidin peptide LL-37 inhibits pancreatic cancer growth by suppressing autophagy and reprogramming of the tumor immune microenvironment. Frontiers in Pharmacology. 2022;13:906625. PMC

  25. Thapa RK, et al. The potential of human peptide LL-37 as an antimicrobial and anti-biofilm agent. Molecules. 2021;26(11):3227. PMC