Cationizing Lugdunin through Trp ³ Hydrophobic Fine-Tuning and Cationic Side Chain Engineering

Lugdunin, a nonpolar cyclic peptide antibiotic, features a unique structural core, making it particularly rare and promising in the landscape of antibiotic discovery. However, its inherent structural limitations have severely hindered its further optimization and clinical translation. To break through these limitations, we employed a combination of Tryptophan³ (Trp³) hydrophobic fine-tuning and cationic engineering strategies to cationize Lugdunin and synthesized a series of cationic Lugdunin derivatives. Among them, W17 demonstrated remarkable antibacterial activity against pathogens like Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), rapid bactericidal action and a low propensity to induce resistance. This stems from a synergistic "membrane disruption-ROS (Reactive Oxygen Species) cascade" dual mechanism acquired via cationization, differing fundamentally from Lugdunin. W17 demonstrated excellent stability and biocompatibility. Crucially, it showed significant therapeutic efficacy in MRSA pneumonia mouse model, strongly supporting its clinical potential. Collectively, Lugdunin cationization markedly enhance its clinical application prospects, offering new antibiotic candidates for combating resistant infections.