Riboflavin-Vancomycin Conjugate Enables Simultaneous Antibiotic Photo-Release and Photodynamic Killing against Resistant Gram-Positive Pathogens

Decades of antibiotic misuse have led to alarming levels of antimicrobial resistance, and the development of alternative diagnostic and therapeutic strategies to delineate and treat infections is a global priority. In particular, the nosocomial, multi-drug resistant “ESKAPE” pathogens such as Gram-positive methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus spp (VRE) urgently require alternative treatments. Here, we developed light-activated molecules, based on conjugation of the FDA-approved photosensitizer riboflavin to the Gram-positive specific ligand vancomycin, to enable targeted antimicrobial photodynamic therapy. The riboflavin-vancomycin conjugate proved to be a potent and versatile antibacterial agent, enabling the rapid, light-mediated, killing of MRSA and VRE with no significant off-target effects. The attachment of riboflavin on vancomycin also led to an increased in antibiotic activity against S. aureus and VRE. Simultaneously, we evidenced for the first time that the flavin sub-unit undergoes an efficient photo-induced bond cleavage reaction to release vancomycin, thereby acting as a photo-removable protecting group for drug-delivery.