Design of a multimodal synthetic peptide antibiotic derived from human cathelicidin

The global rise of multidrug-resistant Acinetobacter baumannii 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.