Design, synthesis, and evaluation of membrane-targeted resveratrol-antimicrobial peptide mimic conjugates for MRSA-infected wound healing.

Abstract

Wound infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are notoriously difficult to treat due to biofilm formation and multidrug resistance, necessitating the development of novel antimicrobial agents. To address this challenge, we designed and synthesized a series of resveratrol-antimicrobial peptide mimic conjugates using a molecular splicing strategy. Among them, lead compound III-5 exhibited a minimum inhibitory concentration (MIC) of 6.25 μg/mL against MRSA, which is an approximately 40-fold improvement in antimicrobial activity over the precursor resveratrol. Moreover, III-5 demonstrated low hemolytic activity, a low propensity to induce drug resistance, and favorable anti-inflammatory properties. The membrane-targeted III-5 effectively disrupted bacterial cell membrane integrity and significantly inhibited both biofilm formation and the eradication of preformed mature biofilms. Transcriptomic analysis indicated a membrane-targeted mechanism, interfering with lipoteichoic acid biosynthesis, cell wall organization, and two-component systems. Together, these membrane-targeted actions synergistically impair cell wall integrity and suppress biofilm formation. Furthermore, in a murine model of MRSA-infected wounds, treatment with III-5-loaded PVA-SA hydrogel achieved a 96% wound healing rate by day 14, significantly accelerating wound closure and reducing the bacterial burden. Collectively, these findings position resveratrol-antibacterial peptide mimic conjugates as a promising antimicrobial candidate for combating MRSA-associated wound infections and provide valuable insights for the development of novel antimicrobial agents.