Increasing antibiotic activity by rapid bioorthogonal conjugation of drug to resistant bacteria using an upconverted light-activated photocatalyst

-sensitized upconversion nanocrystal (UCNC) decorated with toluidine blue O (TB) on its surface undergoes upconverted energy transfer from the UCNC to TB when excited by 808 nm light. The photoexcited TB then catalyses the conversion of the dihydrotetrazine (dHTz) moiety in a Van-dHTz conjugate system to tetrazine which undergoes an efficient inverse electron demand Diels-Alder reaction with prior attached norbornene molecules on bacterial cell walls. The enhanced affinity of Van to bacteria by covalent bonding improves the activity of the drug against drug-resistant Enterococci, and the MIC is reduced by 6- to 7-fold as compared to neat Van. We demonstrate that the mode of action is due to increased inhibition of peptidoglycan cell wall biosynthesis. The findings in this study demonstrate that on-demand NIR-light activated bioorthogonal conjugation of Van to microbes is a viable alternative treatment in combating drug-resistant bacteria.