薬剤耐性菌に対する抗生物質の有効性を増強するためのポリカテコール生体ダイマーの設計

Catechol-modified polymers, such as DOPA-functionalized systems, have recently gained significant interest for a variety of biomedical applications, particularly in their role as antibacterial adjuvants due to their oxidative activity and ability to generate reactive oxygen species (ROS). Current catechol-functionalized polymers, however, often suffer from a restricted number of catechol groups, limited biocompatibility and solubility, and low stability due to the rapid oxidation under physiological conditions. In this study, we developed a water-soluble, biocompatible DOPA-modified biodynamer (DOPA-BD), leveraging the principles of constitutional dynamic chemistry (CDC). DOPA-BD was synthesized via polycondensation of DOPA-hydrazide and the hexaethylene glycol-conjugated carbazole dialdehyde (CA-HG), forming dynamic imine and acylhydrazone linkages between the monomers. As a result of its dynamic covalent backbone, DOPA-BD exhibits biodegradability and undergoes pH-responsive degradation under mildly acidic conditions typically found at infection sites, leading to a more than 3-fold increase in DOPA-hydrazide release compared to physiological pH. Interestingly, driven by CDC, DOPA-BD folds into a nanorod structure with a hydrodynamic diameter of ∼7.8 nm, surrounded by HG chains that offer water solubility and biocompatibility. Moreover, the incorporation of the DOPA-derivative in each repeating unit yields a polymer with exceptionally high catechol content, which remains stable and resistant to oxidation for 72 h in physiological buffer conditions. Regarding its antibacterial applicability, DOPA-BD demonstrated synergistic antibacterial activity with Azithromycin (AZM) against AZM-resistant E. coli, enhancing the antibiotic's efficacy by 4-fold. Our study indicates that DOPA-BD induces ROS production in the respective bacterial strain, suggesting ROS generation as one of the possible mechanisms contributing to the observed synergy. Overall, DOPA-BD represents a promising alternative strategy to potentiate antibacterial activity against resistant strains, holding strong potential for future antibacterial applications.