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.