Redefining Photosensitizers Functionality Through Consensus-Assisted Integration of Orthogonal Antibacterial Mechanisms.

Abstract

Photodynamic antimicrobial therapy (PDAT) offers a promising bactericidal strategy via light-triggered reactive oxygen species (ROS), yet conventional photosensitizers (PSs) typically lack sustained inhibitory activity. Herein, we attempt to redefine the functionality of PSs through a consensus-assisted design strategy that integrates deep learning and molecular docking to embed orthogonal antibacterial mechanisms into a single PS molecule. Specifically, a near-infrared hemi-cyanine PS IHcy-OH is found to unite PDAT with interference of filamentous temperature-sensitive mutant Z (FtsZ) protein, which is essential for bacterial division. By conjugating IHcy-OH with a responsive arm, IHcy-PbE is rationally designed and synthesized to achieve infection responsiveness, rapid light-controlled bactericidal activity, and long-time bacterial inhibition. While such integration typically requires complex multi-component platforms, this strategy successfully unlocks the multifunctional potential of a single PS molecule. Consistent with its design, IHcy-PbE could inhibit methicillin-resistant S. aureus (MRSA) in the dark and exert robust PDAT efficacy upon exposure to hydrogen peroxide and light. This work helps to transform PSs from ROS-dependent killing agents into therapeutics with orthogonal antibacterial mechanisms, establishing a proof-of-concept for a generalizable PSs design paradigm.