Abstract

Antimicrobial peptides (AMPs) are promising alternatives to overcome antimicrobial resistance (AMR). However, precise construction of an AMP targeting bacterial cell membranes derived from natural peptides remains a great challenges. Although the artificial intelligence (AI) algorithm-assisted screening method has achieved unprecedented successes, it's difficult to predict the targets of AMPs obtained from this method. To address this, an AMP ( P 3-3R-8I ) based on several natural peptides derived from insect cuticle was constructed precisely via amino acid mutation. The mutated amino acids Arginine (R) and Isoleucine (I) are expected to target the bacterial cell membranes. Surprisingly, P 3-3R-8I exhibits super antibacterial capability against two representative bacteria: methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli ( E. coli ), which could be attributed to the ability to quickly penetrate bacterial cell membranes and then to bind to bacterial DNA of P 3-3R-8I , resulting in the suppression of DNA replication. In rats’ model, the MRSA-infected wound could be alleviated by P 3-3R-8I obviously, as well as lung and spleen infections in MRSA-induced systemic sepsis. Our findings provide a prospect for the precise construction of AMPs targeting bacterial cell membranes as well as a means of overcoming AMR, offering a strategy for drug-resistant bacteria-induced tissue repair.