Ll 37: Mechanism of Action

Mecanismo de Acao

Primary Antimicrobial: "Carpet-Like" Membrane Disruption

LL-37 disrupts bacterial membranes via electrostatic attraction to anionic bacterial surfaces → hydrophobic insertion → toroidal pore formation or micellization ("carpet-like" mechanism). It acts preferentially on Gram-negative bacteria but is eficaz against ambos(as) Gram-positive and drug-resistant strains. Eukaryotic membranes are protegeu by alto(a) cholesterol content.[3][7]

Receptor Targets

Receptor	Type	Functional Effect
FPR2/FPRL1	GPCR	Chemotaxis of neutrofilos, monocitos, T cells (Yang et al., 2000)[8]
P2X7	Purinergic	IL-1β processing; neutrofilo survival (Elssner et al., 2004)[8]
EGFR	Receptor Tyrosine Kinase	Transativacao → queratinocito migration → cicatrizacao de feridas (Tokumaru et al., 2005)[9]
IGF-1R	Receptor Tyrosine Kinase	Partial agonist → proliferacao (Girnita et al., 2012)[10]
CXCR2	Chemokine	Functional ligand on neutrofilos (Zhang et al., 2009)[8]
MrgX2	GPCR	Mast cell degranulation (Subramanian et al., 2011)[8]
TLR9	Toll-like Receptor	DNA-LL-37 complexes trigger endosomal TLR9 (Lande et al., 2007)[10]

Downstream Signaling Cascades

• ERK1/2 and p38 MAPK: Crucial for queratinocito migration and cicatrizacao de feridas; modula cytokine production in monocitos.[9]
• PI3K/Akt → CREB: Cell survival signaling via P2X7–SFK–Akt pathway in queratinocitos.[9]
• mTOR: Activation suprime autofagia in pancreatic cancer → ROS accumulation → DNA damage.[11]
• NF-κB: Inhibits p50/p65 translocation in inflamacao (anti-inflamatorio(a)); may activate in algum(a) cancers (context-dependent).[8]

Anti-Biofilm Activity

Inhibits quorum-sensing (Las/Rhl systems) and promove twitching motility; eficaz at sub-MIC concentrations (0.5 µg/mL) — far below bactericidal thresholds.[7]

LPS Neutralization

Binds and neutralizes lipopolysaccharide (LPS), preventing endotoxin-induziu macrofago ativacao and cytokine storm.[12]

Biphasic Dose-Response

LL-37 exibe a distinct bell-shaped dose response: ≤1 µM = anti-apoptotico(a), pro-healing; >10 µM = cytotoxic. Em ensaios clinicos, 0.5 mg/mL was 6-fold mais effective do que placebo, enquanto the highest dose (3.2 mg/mL) showed no improvement.[5]

vs. Related Compounds

Compound	Key Difference
hCAP18	Inactive 18 kDa precursor; LL-37 e o(a) ativo(a) C-terminal domain released by proteolise
KR-12	Truncated fragment (residues 18–29); retains antimicrobial activity with menos cytotoxicity
D-LL-37	Protease-resistant enantiomer; retains antimicrobial and anti-biofilm activity
CRAMP (mouse)	Murine ortholog; functional homology but non-identical sequence