Structure-optimized poly(α-amino acid)-based antimicrobial peptide mimetics with balanced bactericidal activity and biosafety for MRSA peritonitis therapy

Developing novel antimicrobial peptide (AMP) mimetics is a crucial approach to addressing the growing problem of bacterial resistance by inheriting the antibacterial advantages of AMPs while overcoming their inherent limitations. However, improperly controlled positive charges and hydrophobic structures in AMP mimetics can lead to strong cytotoxicity. Therefore, achieving high antibacterial efficacy while maintaining favorable biocompatibility is a crucial challenge for AMP mimetics. Herein, based on poly-α-L-lysine (PLL), which possesses potential for biological applications, we introduced varying numbers of aryl side chains to prepare a series of poly (α-amino acids)-based AMP mimetics. Through structure-activity relationship (SAR) studies modulating the balance between positive charge and hydrophobic units, we identified PAA-1, which exhibits a favorable balance between antimicrobial activity and biocompatibility. In vitro antibacterial studies demonstrated that PAA-1 exhibits potent activity against drug-resistant bacteria and biofilm compared to vancomycin, with negligible toxicity. Mechanistic studies suggested that PAA-1 inherits the membrane-damaging mechanism of AMP and shows no drug resistance after 14 consecutive passages. In vivo studies indicated that PAA-1 exhibits superior therapeutic efficacy against Methicillin-resistant Staphylococcus aureus (MRSA)-induced peritonitis, providing greater survival protection compared to vancomycin, with a 7-day survival rate of 80% and demonstrating favorable biosafety. This study constructed AMP mimetics with a balanced antibacterial-biocompatibility profile by optimizing SAR. This provides a referable methodology for discovering more effective AMP mimetics and offers a preclinical research protocol for peritonitis treatment.