Highly Efficient Thiol-Michael Addition Post-Modification toward Potent Degradable Antibacterial Polyesters with Guanidine Moiety

We have previously synthesized poly(3-methylene-1,5-dioxepan-2-one) (PMDXO) that could be modified through the thiol-Michael addition reaction to afford versatile degradable polymers. Herein, we find that the γ-oxa in PMDXO exerts a dramatically accelerating effect on the thiol-Michael addition post-modification, which makes PMDXO a promising platform polymer for synthesizing guanidinium-functionalized aliphatic polyesters under mild and approximately stoichiometric conditions. The relationship between polymer structure and antibacterial performance was investigated. A promising cationic polyester, P20-2C, which shows extremely low hemolytic activity, moderate cytotoxicity, and broad-spectrum potent bactericidal capability against 214 clinically isolated ESKAPE strains, is obtained. The good biocompatibility and potent in vivo antibacterial efficacy of P20-2C have been demonstrated in mice using three bacterial infection models, including MDR E. coli-infected peritonitis and MRSA-infected subcutaneous abscess and skin wound. Finally, a multimodal bactericidal mechanism of membrane disruption plus reactive oxygen species upregulation is proposed for P20-2C against E. coli and S. aureus.