Research in plain language

LL-37

What it is

LL-37 is the only human cathelicidin antimicrobial peptide, a 37-residue cationic alpha-helical peptide released from the hCAP-18 precursor in neutrophils, keratinocytes and epithelia. It is studied for direct broad-spectrum killing of bacteria and fungi by membrane disruption, for neutralizing bacterial LPS (endotoxin) and dampening inflammatory cytokines, and for promoting skin wound re-epithelialization and angiogenesis.

How studies used it

Model: Cell-free / bacterial culture (in vitro)
Studied for: Broad-spectrum antibacterial activity (Gram-negative and Gram-positive) and LPS/endotoxin binding
Dose: In vitro: MIC less than 10 micrograms/mL (about <2.2 micromolar, MW ~4493) against P. aeruginosa, S. typhimurium, E. coli, L. monocytogenes, S. epidermidis, S. aureus and vancomycin-resistant enterococci
Dosing: Single exposure, broth microdilution and radial diffusion assays
Route: in vitro
Duration: Standard overnight susceptibility incubation

Effects measured: MIC under 10 micrograms/mL against the listed pathogens even in 100 mM NaCl. Activity against MRSA, Proteus mirabilis and Candida albicans was lost at 100 mM NaCl but present in low-salt medium; Burkholderia cepacia was fully resistant. LL-37 permeabilized both outer and inner membranes of E. coli ML-35p and bound E. coli O111:B4 LPS with high affinity and positive cooperativity (Hill coefficient 2.02). Generally less potent than protegrin PG-1.

Side effects: Not applicable (cell-free/bacterial assay); salt-dependent loss of activity noted as a limitation

Sources: Turner J, et al. Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils. Antimicrob Agents Chemother. 1998;42(9):2206-14.

Model: Cell culture / yeast (in vitro), 10 clinical strains of Candida auris
Studied for: Antifungal activity against multidrug-resistant Candida auris
Dose: In vitro: MIC 25-100 micrograms/mL (about 5.6-22 micromolar); MFC 50-200 micrograms/mL
Dosing: Single exposure, broth microdilution; drug combinations tested at 1:1 ratio
Route: in vitro
Duration: Standard antifungal susceptibility incubation

Effects measured: MIC 25-100 micrograms/mL and fungicidal concentration 50-200 micrograms/mL across 10 strains. Combined 1:1 with antifungals gave 70% synergy with fluconazole and 100% synergy with both amphotericin B and caspofungin, with no antagonism. Propidium iodide uptake and scanning electron microscopy showed membrane permeabilization and surface disruption; LL-37 raised antioxidant-enzyme activity (oxidative stress) and arrested cells in S phase.

Side effects: No mammalian-cell cytotoxicity or hemolysis was measured in this study; the authors flag this as a gap requiring future work

Sources: Rather IA, et al. Antifungal Activity of Human Cathelicidin LL-37 by Triggering Oxidative Stress and Cell Cycle Arrest in Candida auris. J Fungi (Basel). 2022;8(2):204.

Model: Human keratinocyte line (HaCaT, in vitro) plus mouse (ob/ob) excisional wounds in vivo
Studied for: Wound healing (keratinocyte migration and re-epithelialization)
Dose: In vivo dose not expressed per kg: LL-37 was delivered by adenoviral gene transfer into the wound, not as a weighed peptide dose, so no mg/kg figure exists. In vitro keratinocyte assays used micromolar LL-37 (low-micromolar range).
Dosing: Single in-wound adenoviral delivery (in vivo); single peptide exposure for cell assays
Route: in vitro (cells) and intradermal/in-wound adenoviral transfer (mice)
Duration: Wound-healing follow-up over the excisional-wound closure period

Effects measured: In vitro, LL-37 activated HaCaT keratinocyte migration with actin remodeling, increased tyrosine phosphorylation of focal adhesion kinase and paxillin, induced Snail/Slug transcription factors, activated matrix metalloproteinases, and engaged MAPK and PI3K/Akt signaling (via EGFR transactivation and FPRL-1 induction). In vivo, adenoviral LL-37 transfer to excisional wounds in ob/ob mice significantly improved re-epithelialization and granulation-tissue formation versus control.

Side effects: No adverse events reported in this study

Sources: Carretero M, et al. In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J Invest Dermatol. 2008;128(1):223-36.

Model: Mouse (adult male BALB/c), MRSA-infected surgical back wounds; 80 mice in 8 groups of 10
Studied for: MRSA-infected wound healing and bacterial clearance
Dose: 1 mg/kg LL-37 (given topically and/or intraperitoneally); teicoplanin comparator at 7 mg/kg
Dosing: Treatment started 24 hours after infection
Route: topical and/or intraperitoneal
Duration: 14 days

Effects measured: Untreated infected wounds reached 7.8 x 10^7 CFU/g. Combined topical plus intraperitoneal LL-37 reduced counts to 6.9 x 10^2 CFU/g (significant vs untreated and vs single-route, p<0.05 to p<0.001), close to teicoplanin combined (3.0 x 10^2 CFU/g). Histology of the combined-LL-37 group showed increased re-epithelialization, granulation tissue, collagen organization and angiogenesis (VEGF expression and micro-vessel density).

Side effects: Intraperitoneal LL-37 was reported as safe with no toxic side effects observed

Sources: Simonetti O, et al. Efficacy of Cathelicidin LL-37 in an MRSA Wound Infection Mouse Model. Antibiotics (Basel). 2021;10(10):1210.

Model: Mouse, cecal ligation and puncture (CLP) polymicrobial sepsis model
Studied for: Sepsis / immunomodulation (macrophage pyroptosis, cytokines, survival)
Dose: 2 micrograms per mouse IV (a 1 microgram per mouse dose was also tested and was less effective). Body weight was not reported, so a per-kg value cannot be derived without assumption; at a typical ~20 g BALB/c mouse this is roughly 0.1 mg/kg (estimate only, weight not stated in the paper).
Dosing: Single intravenous dose given immediately after CLP surgery
Route: intravenous
Duration: Single dose; survival followed to 7 days, mediator/bacteria sampling at 15 hours

Effects measured: 7-day survival rose from 6.7% (CLP control) to 36.4% with LL-37 (p<0.05). At 15 hours LL-37 lowered serum IL-1beta (230 to 49 pg/mL, p<0.001), serum IL-6 (92 to 77 ng/mL, p<0.001) and serum TNF-alpha (521 to 308 pg/mL, p<0.05), inhibited caspase-1 activation and peritoneal-macrophage pyroptosis, and reduced bacterial burden in peritoneal fluid (2.5 to 0.7 x 10^9 CFU/mL, p<0.001) and blood (4.2 to 1.8 x 10^5 CFU/mL, p<0.05).

Side effects: No adverse effects reported in this study

Sources: Hu Z, et al. Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice. Int Immunol. 2016;28(5):245-53.

Model: Human, adults with hard-to-heal chronic venous leg ulcers (n=34); first-in-man Phase I/IIa
Studied for: Chronic venous leg ulcer healing
Dose: Topical wound application of LL-37 at 0.5, 1.6 or 3.2 mg/mL solution. This is an applied wound concentration, not a systemic body-weight dose; no mg/kg basis applies and no body weight was used for dosing.
Dosing: Twice weekly applications; 3-week placebo run-in then 4-week randomized double-blind treatment
Route: topical
Duration: 4-week treatment phase plus 4-week follow-up

Effects measured: Healing rate constants were about 6-fold (0.5 mg/mL, p=0.003) and 3-fold (1.6 mg/mL, p=0.088) higher than placebo. Mean ulcer area fell 68% (0.5 mg/mL) and 50% (1.6 mg/mL). The highest concentration (3.2 mg/mL) showed no benefit over placebo, consistent with LL-37 cytotoxicity at higher concentrations.

Side effects: No safety concerns for local or systemic adverse events; treatment was safe and well tolerated

Sources: 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 Regen. 2014;22(5):613-21.

Model: Human, adults with hard-to-heal venous leg ulcers (n=148, mean age 67.6 y, mean wound 11.6 cm2); Phase IIb HEAL, multicentre
Studied for: Chronic venous leg ulcer healing (confirmatory trial)
Dose: Topical LL-37 at 0.5 or 1.6 mg/mL plus compression. Applied wound concentration, not a systemic per-kg dose.
Dosing: Topical, in combination with compression therapy (double-blind, placebo-controlled, three arms)
Route: topical
Duration: Trial treatment and healing-assessment period (as per protocol)

Effects measured: Negative on the primary analysis: no significant improvement in healing for LL-37 vs placebo in the full population. A post hoc subgroup of large ulcers (at least 10 cm2) showed significant improvement in several interrelated healing parameters, but this was not the prespecified endpoint and needs a powered confirmatory trial.

Side effects: Study drug was well tolerated and safe at both 0.5 and 1.6 mg/mL

Sources: 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.

How solid the evidence is

Mixed quality, and honestly the human wound-healing evidence is the weak point. The antimicrobial in-vitro data are solid and reproducible: the Turner 1998 study (PMID 9736536) is a foundational, well-cited methods paper showing MIC under 10 micrograms/mL against several pathogens, but it also exposes LL-37's biggest in-vitro caveat, that activity drops sharply at physiological salt (100 mM NaCl) for MRSA, Proteus and Candida. The Candida auris antifungal paper (PMID 35205958) is a single-group in-vitro study from one lab with no mammalian-cell cytotoxicity controls, which the authors themselves flag, so the synergy and S-phase-arrest claims are preliminary. Animal data (PMID 34680791 MRSA wound; PMID 26746575 CLP sepsis) are small single-experiment rodent studies with strong p-values but modest absolute survival gains (sepsis survival only 6.7% to 36.4%) and short follow-up; the sepsis dose is reported as 2 micrograms per mouse with no body weight stated, so any mg/kg figure is an estimate, not a published per-kg dose. The Carretero wound study (PMID 17805349) delivered LL-37 in vivo by adenoviral gene transfer, not as a weighed peptide, so it cannot be translated into a dose at all. For humans there are two randomized controlled trials and they disagree: the first-in-man Phase I/IIa (PMID 25041740, n=34, sponsor Pergamum/Promore) was positive at the two lower topical concentrations with a clear bell-shaped dose-response (the highest 3.2 mg/mL dose failed, consistent with self-cytotoxicity), but the larger confirmatory Phase IIb HEAL trial (PMID 34687253, n=148, same sponsor lineage, drug name ropocamptide) was NEGATIVE on its primary endpoint, with only a post hoc large-ulcer subgroup signal. Both human trials were sponsor-run. Net: good antimicrobial and immunomodulatory mechanism evidence, but the clinical wound-healing benefit is unproven, the only adequately powered human trial failed, and all human dosing is a topical wound concentration (mg/mL), never a systemic per-kg dose. Safety across studies was consistently benign at the doses used, with the notable caveat that LL-37 is cytotoxic to mammalian cells at higher concentrations.

Sources

Study data, research use only. No established human dosing protocol.