Structure-activity relationship screening of poly(L-ornithine)-based antimicrobial peptide mimetics for peritonitis...

Peritonitis is commonly encountered in clinical settings, such as intra-abdominal infection, abdominal surgery, and peritoneal dialysis-associated infection. It progresses rapidly and remains difficult to treat. Antimicrobial peptides (AMPs) exhibit broad-spectrum antibacterial activity and a low potential to induce resistance; however, natural peptides are readily degraded by proteases, which limits their applications in complex infectious environments. Poly(L-ornithine) (PLO) contains a non-natural amino acid structure and exhibits favorable enzymatic stability and cationic characteristics, making it a promising backbone for constructing AMP mimetics. In this study, a series of PLO-based derivatives (PLO(m)) were synthesized, and the relationship between the degree of hydrophobic modification and both antibacterial activity and biocompatibility was systematically evaluated. Specifically, cyclobutyl hydrophobic groups were introduced into the side chains in different proportions. The results showed that PLO(20%) provided the optimal compromise between antibacterial efficacy and safety. Its antibacterial action was primarily attributed to the disruption of bacterial membrane integrity, and its activity was not affected by pH, salt ions, or proteases. Moreover, PLO(20%) effectively suppressed biofilm formation and could eliminate established biofilms. In a mouse methicillin-resistant Staphylococcus aureus (MRSA) peritonitis model, PLO(20%) reduced bacterial burdens in the peritoneal cavity and major organs and improved survival, with no obvious tissue toxicity observed. These findings indicate that regulating the hydrophobic modification ratio of PLO is an effective strategy to obtain efficient and safe AMP mimetics, providing a promising candidate material for the treatment of complex infections such as peritonitis.