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

19 May 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


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.


photodynamic therapy
photolabile protecting groups
drug delivery
antimicrobial resistance
ESKAPE pathogens

Supplementary materials

Supplementary information
Additional synthetic schemes and procedures, materials, methods, experimental and characterization details. This includes 1H NMR, HPLC and HR-MS data. Additional UV-Vis, fluorescence and kinetic plots, details of photophysical and photochemical setups and characterisations methods. Additional biology materials, methods and assay procedures, growth curves and mammalian cell data.


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