Cholesteryl Succinate-Modified Antimicrobial Peptides for Selective Sterilization of Staphylococcus aureus in Photodynamic Therapy

The evolution of antibiotic resistance poses a great challenge to the bacterial infectious disease therapy. Although antimicrobial peptides and photodynamic therapy have great potential in the treatment of bacteria, their clinical application is limited due to high toxicity and low therapeutic efficiency. Herein, an innovative nano antibacterial agent was designed based on cationic antimicrobial peptides (AMPs) modified with cholesterol succinate to load the hydrophobic photosensitizer TCPP (ACT) for selective killing of S. aureus. The modification of cholesterol succinate significantly increased the positive charge of AMPs while decreasing toxicity and hemolysis. The increased positive charge could capture bacteria through electrostatic interaction, which reduced the distance between the photosensitizer and bacteria to enhance the photodynamic sterilization effect. ACT selectively killed S. aureus, not E. coli, and showed excellent destruction and inhibition ability for S. aureus-formed biofilm. ACT accelerated wound healing by promoting collagen precipitation and angiogenesis after good bacterial clearance in mice with S. aureus-infected wounds. This strategy provides a paradigm for addressing toxicity and broadening the application of antimicrobial peptides and photosensitizers.