How do antimicrobial peptides kill bacteria without harming human cells?

Antimicrobial peptides such as LL-37 exploit structural differences between prokaryotic and eukaryotic cell membranes. Bacterial membranes are typically negatively charged due to the predominance of anionic phospholipids such as phosphatidylglycerol and cardiolipin on their outer leaflet, and they lack cholesterol. Human cell membranes present a zwitterionic outer leaflet (predominantly phosphatidylcholine and sphingomyelin) and contain substantial cholesterol, which stabilises membrane structure. Cationic amphipathic peptides like LL-37 are electrostatically attracted to negatively charged bacterial membranes and insert into them to form pores or cause membrane disruption via carpet or toroidal-pore mechanisms. The cholesterol-rich human membrane is substantially more resistant to these disruption mechanisms, providing a degree of selectivity. Selectivity is not absolute, and concentration-dependent toxicity to eukaryotic cells occurs at higher concentrations, which is a key factor in the therapeutic window relevant to any clinical application.

What distinguishes LL-37 from other antimicrobial peptides such as defensins?

Humans express two major families of antimicrobial peptides as part of innate immunity: cathelicidins and defensins. LL-37 is the sole human cathelicidin, encoded by the CAMP gene and processed from the hCAP18 precursor by serine proteases. Its 37-amino acid alpha-helical structure is amphipathic, with hydrophobic and cationic faces that insert into bacterial membranes. Human defensins (alpha-defensins produced by neutrophils and Paneth cells, and beta-defensins produced by epithelial cells) are structurally distinct: they are smaller peptides (18-45 amino acids) with a characteristically folded beta-sheet structure stabilised by three intramolecular disulfide bonds. Defensins disrupt membranes by different structural mechanisms. LL-37 has additional immunomodulatory activity beyond membrane disruption, including TLR4 and TLR9 signalling modulation, chemokine receptor activation, and angiogenesis promotion, roles not shared by defensins to the same degree.

Is LL-37 approved for clinical use?

LL-37 is not approved as a therapeutic agent by the FDA, EMA, or other major regulatory bodies. Clinical investigations have examined wound healing applications, particularly in chronic venous leg ulcers, via intradermal and topical administration routes. No regulatory approval for human therapeutic use has been granted at the time of publication. LL-37 is available from peptide research suppliers as a research chemical in lyophilised form. Possession and use regulations vary by jurisdiction.

Peptide class

Antimicrobial Peptides

Cationic, amphipathic peptides that disrupt microbial membranes directly and modulate innate immune signalling, including the only known human cathelicidin, LL-37.

Compound	Mechanism	Primary reported use	Profile
LL-37 (Human Cathelicidin)	Amphipathic alpha-helical membrane disruption; TLR4 and TLR9 modulation; promotes keratinocyte migration and angiogenesis	Antimicrobial activity, wound healing, innate immune modulation	View profile

How This Class Works

Antimicrobial peptides (AMPs) are short peptides, typically fewer than 50 amino acids, that are produced as part of innate immunity across virtually all domains of life. Their defining structural feature is amphipathicity: the peptide chain arranges itself so that hydrophobic residues cluster on one face and cationic (positively charged) residues on the other. This architecture allows AMPs to electrostatically target negatively charged bacterial and fungal cell membranes while being repelled by the predominantly neutral outer leaflet of mammalian cells. Upon membrane contact, AMPs insert into the lipid bilayer, where they form pores, fragment the membrane via a carpet-like mechanism, or trigger membrane curvature and disruption through the toroidal-pore model, depending on the specific peptide and membrane composition.

LL-37 is the only human cathelicidin. It is derived from the precursor protein hCAP18 (human cationic antimicrobial protein of 18 kDa), which is encoded by the CAMP gene and stored in neutrophil secondary granules and other immune cells. Upon activation, serine proteases cleave hCAP18 to release the mature 37-amino acid C-terminal fragment known as LL-37, named for the two N-terminal leucine residues and total peptide length. The mature peptide adopts an alpha-helical conformation in the presence of membranes, and this helix is amphipathic, with a hydrophobic face and a cationic face separated by approximately 180 degrees. The cationic residues are attracted electrostatically to the anionic bacterial membrane; the hydrophobic face inserts into the hydrophobic core of the lipid bilayer, disrupting structural integrity and causing leakage or lysis.

Beyond direct membrane disruption, LL-37 has pleiotropic immunomodulatory roles. It binds and neutralises lipopolysaccharide (LPS), dampening excessive TLR4-mediated inflammatory responses to gram-negative bacteria. It also modulates TLR9 signalling, interacts with the chemokine receptor FPRL1 (also known as FPR2), promotes keratinocyte migration relevant to wound re-epithelialisation, and upregulates angiogenic signalling including VEGF pathways. These secondary roles overlap substantially with those of peptides in the thymosin class, such as TB-500, though the upstream mechanisms are distinct.

Research Context

The cathelicidin family was characterised in the 1990s following identification of a conserved cathelin domain in neutrophil antimicrobial proteins across mammals. While most mammals express multiple cathelicidins (rodents express at least six), humans were found to express only a single cathelicidin gene, CAMP. The unique single-cathelicidin phenotype in humans is thought to have arisen through evolutionary gene reduction, with LL-37 representing the sole endogenous representative of this class in human biology.

Clinical investigation of LL-37 has focused on wound healing applications. A Phase 1/2 study examined intradermal injection of LL-37 in patients with chronic venous leg ulcers, with findings suggesting improved wound closure rates. Topical application research has been limited by challenges related to peptide stability in the wound environment and degradation by wound proteases. No regulatory approval for any LL-37 formulation has been granted at the time of publication. Research has also investigated LL-37's potential role in inflammatory skin conditions, given that LL-37 expression is markedly upregulated in psoriatic skin, a finding that has prompted investigation of both LL-37 as a therapeutic target and as a therapeutic agent in different skin disease contexts.

Individual Compound Notes

LL-37

The only human cathelicidin; active against gram-positive and gram-negative bacteria, fungi, and some enveloped viruses. Research has investigated subcutaneous and intradermal injection for wound healing and innate immune support. Anecdotal research accounts typically describe doses of 100 to 200 mcg subcutaneously. Distinct from defensins and thymosin peptides in mechanism despite overlapping tissue-repair and immune-related research contexts.