Orthogonal Design of a Guanidinocarbonyl Pyrrole-Functionalized Pillar[5]arene-Based Adjuvant for Synergistic...

An orthogonal strategy is employed to synthesize the antibacterial adjuvant GCPP5 through functionalization of pillar[5]arene with guanidinocarbonyl pyrrole (GCP) units. This design enables the construction of a supramolecular nanoassembly (GCPP5⊃CFZ⊃EsY-CN) for multimodal treatment of Staphylococcus aureus (S. aureus) infections. The system integrates a membrane-targeting GCP group, the antibiotic cefazolin (CFZ), and a photosensitizer eosin Y derivative (EsY-CN) via host-guest interactions, including the binding of CFZ to the nitrogen sites on the GCP moieties and the encapsulation of EsY-CN within the electron-rich cavity of the pillar[5]arene. These programmed interactions realize a multimodal "targeting-chemical inhibition-photodynamic oxidation" antibacterial strategy. Experimental results show that the photoactivated assembly effectively generates reactive oxygen species, eradicates S. aureus at extremely low concentrations (5 to 10 nm), inhibits and eliminates biofilms, and mitigates the increase in the minimum inhibitory concentration during serial-passage assays under the tested conditions. In vivo wound models confirm that the nanoassembly could accelerate the healing process and reduce bacterial load while exhibiting good biocompatibility. By exploiting an orthogonal supramolecular design, this work establishes a promising multimodal antimicrobial strategy for combating light-accessible biofilm-associated infections.