N-Terminal Lipidation of Buforin II Generates a Potent and Stable Peptide Antibiotic.

Buforin II is a broad-spectrum antimicrobial peptide (AMP) that kills bacteria by targeting intracellular nucleic acids. Unlike most membrane-acting AMPs, its unique antibacterial mechanism reduced its cytotoxicity. Nonetheless, its weak antibacterial potency and poor proteolytic stability still limit its clinical translation. Considering its helix-hinge-helix structure, lipidations were performed on its -terminal, generating 5 different analogs. By screening the antibacterial and hemolytic activities, BUFT-2C8 with branched octanoic acid tails was identified as the optimal candidate. Its increased hydrophobicity and helicity not only endowed its improved antibacterial potency and proteolytic stability but also facilitated its enhanced membrane penetrability. Consequently, it displayed comparable inhibition and eradication rates against the biofilm as the commercialized polymyxin B. On the mouse model, it also exerted superior safety and comparable efficiency for the treatment of peritonitis sepsis than polymyxin B, demonstrating a paradigm for the future development of potent peptide antibiotics.