LL-37 kills by physically wrecking membranes rather than by hitting a protein target, and that one structural fact explains both its breadth and its ceiling. The published record supports the mechanism strongly in model membranes and cell culture, and far less strongly at the concentrations human tissue actually reaches, where salt and serum blunt direct killing and immune recruitment appears to carry much of the load. LL-37 is an endogenous human peptide, not an approved drug, and no LL-37 product carries an FDA approval for any indication.
LL-37 is the only cathelicidin humans produce, a 37-residue cationic peptide with a net charge near +6 that kills by binding anionic microbial surfaces and disrupting the lipid bilayer physically, an activity reported against Gram-negative and Gram-positive bacteria, Candida albicans, and enveloped viruses but one that weakens at the 100 to 150 mM sodium chloride of extracellular fluid.
The sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES does its work through arithmetic, with eleven lysine and arginine residues set against five aspartate and glutamate residues. Folding is not a separate step from binding: the peptide stays largely unstructured in dilute aqueous buffer and adopts its helix only on contact with anionic lipids, elevated salt, or other helix-promoting conditions.
The surplus of positive charge left by eleven lysine and arginine residues against five acidic ones is the single property that makes anionic microbial surfaces preferential targets, and the truncated skin fragments RK-31 and KS-30 keep that killing potency while losing parts of the receptor-binding behavior, which locates the antimicrobial function in the helical core rather than the termini.
Two models compete for LL-37, and the mechanism is genuinely contested rather than settled, whatever the shorthand accounts that name only the carpet picture imply. Oriented circular dichroism anchors both sides of the argument, with the same technique at the same peptide-to-lipid ratios read in opposite directions.
Oriented circular dichroism at peptide-to-lipid ratios of 1:50 and 1:100 has shown a substantial fraction of LL-37 helices oriented approximately normal to the bilayer alongside transmembrane pores of roughly 23 to 33 angstrom water channel radius, so the toroidal pore stands as a well-supported model in its own right rather than a minor alternative to carpet-driven collapse.
Selectivity comes down to what sits on the outside of the two kinds of membrane, and it is settled by charge before any hydrophobic interaction begins. A cationic peptide is pulled hard toward one surface and left largely indifferent to the other, with cholesterol and membrane potential widening the gap further.
| Property | Human plasma membrane | Bacterial membrane |
|---|---|---|
| Outer leaflet lipids | Zwitterionic phosphatidylcholine and sphingomyelin | Anionic phosphatidylglycerol and cardiolipin |
| Anionic lipid placement | Phosphatidylserine held on the inner leaflet by flippase | Anionic lipids abundant on the outer surface |
| Outer surface addition | None | LPS in Gram-negative, lipoteichoic acid in Gram-positive |
| Cholesterol | Roughly a quarter to a third of the lipid | Absent from most species |
| Transmembrane potential | Smaller in resting cells | Around -130 to -150 mV |
Selectivity is relative rather than absolute, with hemolysis and epithelial toxicity reported in the tens of micromolar, not far above LL-37's antibacterial range, which is a central reason the natural peptide has proven difficult to develop as a systemic drug.
A large share of it does, and the split has not been quantified. The argument turns on a concentration gap: chemotaxis through the formyl peptide receptor FPR2 runs at nanomolar levels, one to three orders of magnitude below what direct killing typically demands, so the compartment decides which arm is plausibly at work.
LL-37 recruits neutrophils, monocytes, mast cells, and T cell subsets through FPR2 at nanomolar concentrations, one to three orders of magnitude below the levels direct killing requires, and the free peptide available in plasma sits below the killing range, which is why much of the field reads its in vivo anti-infective effect as immune recruitment rather than lysis at the site.
Against enveloped viruses the mechanism runs close to the bacterial one, since a viral envelope is a lipid bilayer taken from the host cell and is therefore permeabilizable. The parallel breaks down on selectivity: envelope lipids carry host composition, so what protects human cells does not protect a virion, and curvature, surface protein density, and the absence of any repair capacity take over as the deciding factors.
| Criterion | Enveloped viruses | Candida albicans |
|---|---|---|
| First binding target | Host-derived lipid envelope | Cell wall carbohydrate, notably mannan |
| Mechanism reported | Envelope disruption; for influenza A, substantially post-entry replication reduction | Wall saturation, then plasma membrane permeabilization |
| Readout | Loss of infectivity | ATP efflux and loss of viability |
| Evidence level | Cell culture, frequently low-salt or serum-free | Cell culture, frequently low-salt or serum-free |
Laboratory studies report LL-37 activity against influenza A, herpes simplex virus type 1, vaccinia, respiratory syncytial virus, human immunodeficiency virus type 1, and Candida albicans, but nearly all of it comes from cell culture at concentrations chosen by the experimenter, so none of it demonstrates that endogenous LL-37 clears these pathogens in people at the levels the body produces.
The gap between the laboratory number and the tissue reality is the whole story here, and salt is the classic reason for it, though its effect falls unevenly across organisms rather than uniformly. Monovalent cations screen the electrostatic attraction that drives the first binding step, and serum, divalent cations, and proteolysis each take another bite out of what remains.
MIC values for LL-37 reported in low-salt, protein-free media are the numbers most often quoted and they systematically overstate what the peptide does in real tissue, where 100 to 150 mM sodium chloride, millimolar magnesium and calcium, and serum protein binding place the killing concentrations out of reach at most sites.
Killing an organism and disarming the toxin it sheds are separate jobs, and this one matters independently, since dead bacteria still release endotoxin and lysis by antibiotics can raise the free LPS burden. LL-37 works on the ligand rather than the receptor, which makes it a scavenger rather than a blocker.
Because LL-37 binds the lipid A anchor of LPS rather than the TLR4 receptor, it blocks the LPS-binding protein handoff to CD14 and the loading of MD-2, so endotoxin signaling is neutralized whether or not the organism dies.
Bacteria carry dedicated countermeasures against this peptide, which is a problem for anyone building a therapy on it. Surface charge is the most common defense and it is manipulated deliberately, with mutants lacking these systems measurably more susceptible than the wild type.
Serial passage under sub-inhibitory peptide has produced stably less susceptible mutants in several species, which undercuts the older claim that membrane-active antimicrobial peptides escape resistance, and raises a concern specific to LL-37 analogs: clinical use could erode part of a patient's own innate immunity.
Evidence for intracellular targets is real but distinctly weaker than the membrane case, and the confound is easy to miss. Membrane depolarization on its own shuts down macromolecular synthesis by collapsing the proton motive force that transport and translation depend on, so a measured drop in protein synthesis proves nothing about a target inside the cell.
No single intracellular target has been established for LL-37 with anything approaching the confidence the membrane mechanism enjoys, and secondary intracellular effects most likely contribute only near the threshold where membranes are perturbed but not yet destroyed.
The striking finding is that the anti-biofilm effect appears well below the killing concentration, which makes it regulatory rather than lytic. Timing decides the outcome, because preventing a biofilm from establishing is a far easier proposition than dismantling a mature one.
LL-37 at roughly 0.5 micrograms per milliliter suppresses Pseudomonas aeruginosa biofilm formation without measurably affecting planktonic growth, an effect traced to quorum sensing downregulation and stimulated twitching motility, though the evidence comes from in vitro flow-cell and microtiter systems in defined media whose relevance to biofilms on tissue or indwelling devices has not been established.
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