High Therapeutic Index α‑Helical AMPs\nand Their Therapeutic Potential on Bacterial Lung and Skin Wound Infections

Antimicrobial peptides (AMPs) possess\nstrong antibacterial activity\nand low drug resistance, making them ideal candidates for bactericidal\ndrugs for addressing the issue of traditional antibiotic resistance.\nIn this study, a template (G(XXKK)<i><sub>n</sub></i>I,\nG = Gly; X = Leu, Ile, Phe, or Trp; <i>n</i> = 2, 3, or\n4; K = Lys; I = Ile.) was employed for the devised of a variety of\nnovel α-helical AMPs with a high therapeutic index. The AMP\nwith the highest therapeutic index, WK<sub>2</sub>, was ultimately\nchosen following a thorough screening process. It demonstrates broad-spectrum\nand potent activity against both standard and multidrug-resistant\nbacteria, while also showing low hemolysis and rapid and efficient\ntime-kill kinetics. Additionally, WK<sub>2</sub> exhibits excellent\nefficacy in treating mouse models of Klebsiella pneumonia-induced lung infections and methicillin-resistant Staphylococcus aureus (MRSA)-induced skin wound infections\nwhile demonstrating good safety profiles <i>in vivo</i>.\nIn conclusion, the template-based design methodology for novel AMPs\nwith high therapeutic indices offers new insights into addressing\nantibiotic resistance problems. WK<sub>2</sub> represents a promising\nantimicrobial agent.