K-174

Antimicrobial peptides have garnered increasing attention and are anticipated to address the growing crisis of antibiotic resistance. However, their inadequate proteolytic stability poses significant challenges for clinical development. In this study, we present a highly effective strategy to overcome the limitations by introducing multiple halogenated sulfono-γ-AApeptides into cationic AMP Feleucin-K3. Surprisingly, K162 and K174, which feature sulfono-γ-AApeptide modifications containing iodinated or trifluoromethyl groups, exhibit powerful antibacterial and antibiofilm activities, while having significantly improved stability. Furthermore, they exhibited low resistance tendencies and were less susceptible to cross-resistance in comparison to antibiotics. Additionally, the two analogs exhibited superior safety and therapeutic potential compared to polymyxin B against pneumonia induced by multidrug-resistant P. aeruginosa. For skin- and catheter-biofilm-related infections caused by MRSA, K162, and K174 displayed comparable therapeutic effects compared to vancomycin. In conclusion, K162 and K174 are considered novel antimicrobial alternatives to combat multidrug-resistant bacterial infections.