Design of a multimodal synthetic peptide antibiotic derived from human cathelicidin

underscores the urgent need for innovative therapeutics. Although peptides have emerged as promising antimicrobial molecules, their clinical application is limited by rapid degradation. Here, we introduce d-GK17, a d-enantiomeric derivative of the human cathelicidin LL-37 engineered to resist proteolysis. This study provides the first comprehensive preclinical validation of an inverso LL-37-derived peptide, demonstrating that d-GK17 displays potent broad-spectrum antimicrobial, antibiofilm, and immunomodulatory effects while maintaining stability in serum and wound environments with a low propensity for resistance development. It also surpasses conventional antibiotics and its L-amino acid counterpart in disrupting established biofilms, collapsing biofilm architecture, and killing biofilm-encased cells. Mechanistically, d-GK17 depolarizes the cytoplasmic membrane, neutralizes lipopolysaccharides, and suppresses NF-κB-mediated inflammation. In murine infection models, d-GK17 significantly reduces bacterial load over extended periods without toxicity. This human-derived inverso peptide establishes a multimodal therapeutic platform, offering a promising pathway for clinical translation to combat antimicrobial resistance.