Hydrophobicity-to-cationic amphipathicity transformable antimicrobial polypeptides for the prevention of medical implant-associated infections

Surface immobilization of antimicrobial peptides (AMPs) on implants offers promising efficacy against drug-resistant bacterial infections. The cationically amphipathic structure of AMPs, while crucial for their potent antimicrobial activity, poses substantial challenges for achieving scalable coatings on implants and contributes to their cytotoxicity toward normal tissues/cells. Herein, we developed hydrophobicity-to-cationic amphipathicity transformable AMPs (HAT-AMPs) for scalable coating on medical implant, effectively preventing bacterial infections while exhibiting low cytotoxicity to normal tissues. The HAT-AMPs, composed of ionizable and hydrophobic residues, are hydrophobic and electrically neutral at physiological pH condition, making them highly suitable for physical immobilization on titanium surfaces while exhibiting minimal toxicity to normal tissues. In acidic environments during infections, the protonation of ionizable units induces HAT-AMPs to adopt a cationically amphipathic structure, remarkably enhancing their antimicrobial activity by targeting bacterial phospholipid phosphatidylglycerol. When immobilized on titanium implant surface, the coating exhibited a favorable safety profile, and demonstrated strong antibacterial efficacy and promising wound-healing potential in a subcutaneous infection mouse model. This strategy offers an efficient approach for fabricating infection-responsive implant coatings.