Disulfide-bonded YC18: A membrane-targeting peptide with superior efficacy against Staphylococcus aureus infections.

The escalating crisis of antimicrobial resistance, particularly in Staphylococcus aureus (S. aureus) infections, demands innovative therapeutics beyond conventional antibiotics. Spider venom represents a rich source of bioactive peptides with untapped therapeutic potential. Here, we report YC18, a novel disulfide-stabilized β-hairpin peptide derived from the cDNA library of Chilobrachys liboensis (C. liboensis). This peptide exhibits potent and selective activity against S. aureus, with a minimum inhibitory concentration (MIC) of 6.25 μg/mL. Unlike vancomycin, YC18 exhibits low resistance development even after 35 serial passages of S. aureus, underscoring its clinical potential. Structural prediction revealed that YC18's unique dual-disulfide scaffold (Cys2-Cys15, Cys6-Cys11) confers exceptional stability and efficacy, as validated by peptide analog studies. Mechanistically, YC18 selectively targets phosphatidylglycerol (PG) to disrupt bacterial membranes, a process elucidated through molecular dynamics simulations. With high plasma stability, low cytotoxicity, and efficacy in murine infection models, YC18 emerges as a promising candidate for combating S. aureus infections.