Host–Guest Antimicrobial Based on Conjugated Oligoelectrolyte and Cyclodextrin

Abstract The escalating global threat of antimicrobial resistance necessitates the development of new antimicrobial agents. In this study, we prepared a resveratrol‐derived antimicrobial conjugated oligoelectrolyte (COE) named DY6 to enhance drug‐like properties. While DY6 ’s increased hydrophobicity augmented its antibacterial efficacy, it also induced significant cytotoxicity, highlighting the long‐existing dilemma of amphiphilic antimicrobials. To mitigate this issue, we employed a supramolecular strategy by complexing DY6 with sodium sulfobutyl ether β‐cyclodextrin ( SβCD ), forming the host–guest inclusion complex DY6@SβCD . This complex elevated the half‐maximal inhibitory concentration (IC 50 ) against L929 cells from 9.4 to over 128 µg mL −1 while maintaining a minimum inhibitory concentration (MIC) of 2 µg mL −1 against methicillin‐resistant Staphylococcus aureus (MRSA). NMR and UV–vis spectroscopic analyses confirmed that DY6 ’s aromatic backbone is encapsulated within the hydrophobic cavity of SβCD . Isothermal titration calorimetry revealed that size compatibility and electrostatic interactions are essential for stable complex formation and enhanced biocompatibility. Importantly, DY6@SβCD exhibited no resistance development over 14‐day serial passages against S. aureus , significantly outperforming norfloxacin. In biofilm‐based MRSA‐infected wound and corneal models, DY6@SβCD more effectively reduced bacterial load and inflammation compared to the last‐resort antibiotic vancomycin. These findings demonstrate the potential utility of supramolecular host–guest approach based on COEs to overcome the drug‐resistant challenges.