Biomimetic antimicrobial peptides capture and kill methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) infections face significant clinical challenges such as antibiotic resistance and biofilm formation. It is necessary to develop novel antimicrobial strategies. In this study, we construct biomimetic antimicrobial peptides (BAMPs), i.e. Stearic acid-FFVLK-irikirik-NH 2 (SAFI) and Linoleic acid-FFVLK-irikirik-NH 2 (LAFI), to mimic the natural human defensin 6 that captures and kills invading bacteria. The peptides are designed with hydrophilic IRIKIRIK sequence for targeting and killing MRSA, FFVLK sequence for fibrillogenesis and hydrophobic chain. Both peptides exhibited potent antibacterial activity against MRSA and other Gram-positive bacteria with the MIC of 8 μM, and inhibited biofilm formation. SEM and TEM images showed that peptides self-assembled into nanofibrous networks that physically entrapped MRSA cells. The peptides induced membrane depolarization, increased permeability, accompanied by ROS accumulation. In a murine full-thickness skin infection model, SAFI and LAFI induced significant bacterial reduction and comparable therapeutic efficacy to vancomycin. What's more, there was no local irritation or systemic toxicity during short-term topical use. The BAMPs show potential as alternatives to traditional antibiotics, particularly for topical applications in MRSA infections. • Biomimetic antimicrobial peptides SAFI and LAFI were rationally designed based on human defensin 6. • SAFI and LAFI effectively prevented biofilm formation and disrupted established biofilms. • SAFI and LAFI exhibited potent antibacterial activities against MRSA and other Gram-positive bacteria. • SAFI and LAFI induced increase of membrane depolarization and permeability.