Green-Light-Activatable Penicillin for Light-Dependent Spatial Control of Bacterial Growth, Biofilm Formation, and In Vivo Infection Treatment

Our ability to prevent, treat, and cure bacterial infections is nowadays seriously threatened by the rise of (multidrug) antimicrobial resistance (AMR), and novel molecular approaches in the antibacterial arsenal are urgently needed. To fight the development of AMR, the field of photopharmacology aims to develop photoresponsive antimicrobials allowing for noninvasive activation of the drug only at the site needed, with spatiotemporal precision, reducing the bacterial exposure to the active antimicrobial in the environment. This study reports the development and application for the first time of a green-light-activatable variant of penicillin (Penicillin-PPG), designed through the incorporation of a photocleavable protecting group. Here, we demonstrate that Penicillin-PPG shows no antimicrobial activity in the dark, while it can be precisely activated through irradiation with green light. Furthermore, we show Penicillin-PPG’s utility to spatially control bacterial growth, achieve light-dependent inhibition of biofilm formation, and showcase the unprecedented usage of a photoactivatable antimicrobial in vivo in a small animal infection model. Furthermore, we apply Penicillin-PPG in combination with a λ-orthogonally photocaged bioactive compound to achieve photocontrol over antimicrobial activity dependent on two distinct colors of light.

A light-activatable penicillin analogue allows for spatial control over bacterial growth and light-dependent inhibition of biofilm formation and rescues larvae in an in vivo small animal infection model.