Light-triggerable and pH/lipase-responsive release of antibiotics and β-lactamase inhibitors from host-guest self-assembled micelles to combat biofilms and resistant bacteria

Major challenges remain in combat with the inevitable rise of intrinsic resistance to antibiotics and biofilm formation. Herein, we explore host-guest self-assembled micelles for light-triggered and stimuli-responsive release of antibiotics and beta-lactamase inhibitors to combat biofilms derived from methicillin-resistant Staphylococcus aureus (MRSA). beta-Cyclodextrin-capped phenylboronic acid-tetraphenylethylene (PBA-TPE) conjugates are coupled with ampicillin (Amp) via reactive oxygen species (ROS)-cleavable thioketal linkers to obtain cd-PTTA prodrug. Adamantane-capped poly(ethylene glycol)-poly(epsilon-caprolactone) (PECL-ad) amphiphilic copolymers are linked with cd-PTTA via host-guest complexation and simultaneously self-assembled into PECL@PTTA micelles. The digestion of poly(epsilon-caprolactone) segments by bacterial lipase destructs micelles and the aggregation-induced emission feature of cd-PTTA leads to ROS generation after light illumination. The produced ROS destroys biofilms and breaks thioketal linkers to release Amp antibiotics, while the pH-responsive removal of beta-cyclodextrin activates the PBA beta-lactamase inhibitors, affording synergistic actions on MRSA. The light illumination and intrinsic signals of acidic pH and lipase display interactive promotions of Amp release, micelle destabilization, and beta-lactamase inhibition. Compared to those of cd-PTTA, the PECL@PTTA micelle treatment under light exposure shows sustained growth inhibition of planktonic MSRA, 2-fold higher elimination rate of biofilms, and 28-fold lower number of live MRSA embedded in biofilms. In an MRSA subcutaneous infection model, the micelle treatment with light exposure could eradicate bacteria and a complete wound closure was observed with normal re-epithelialization and skin morphology. Thus this strategy enables synchronous release of antibiotics and activation of beta-lactamase inhibitors for photodynamic destruction of biofilms and restoration of the antibiotic activity to resistant bacteria embedded.