Exciting Bacteria to a Hypersensitive State for Enhanced Aminoglycoside Therapy by a Rationally Constructed AIE Luminogen

The diminishing effectiveness of existing aminoglycoside antibiotics (AGs) compels scientists to seek new approaches to enhance the sensitivity of current AGs. Despite ongoing efforts, currently available approaches remain restricted. Herein, a novel strategy involving the rational construction of an aggregation‐induced‐emission luminogen (AIEgen) is introduced to significantly enhance Gram‐positive bacteria's susceptibility to AGs. The application of this approach involves the simple addition of AIEgens to bacteria followed by a 5 min light irradiation. Under light exposure, AIEgens efficiently generate reactive oxygen species (ROS), elevating intrabacterial ROS levels to a nonlethal threshold. Post treatment, the bacteria swiftly enter a hypersensitive state, resulting in a 21.9‐fold, 15.5‐fold, or 7.2‐fold increase in susceptibility to three AGs: kanamycin, gentamycin, and neomycin, respectively. Remarkably, this approach is specific to AGs, and the induced hypersensitivity displays unparalleled longevity and heritability. Further in vivo studies confirm a 7.0‐fold enhanced bactericidal ability of AGs against Gram‐positive bacteria through this novel approach. This research not only broadens the potential applications of AIEgens but also introduces a novel avenue to bolster the effectiveness of AGs in combating bacterial infections. A novel approach, utilizing a rationally constructed aggregation‐induced‐emission luminogen (AIEgen), is reported to significantly enhance the susceptibility of Gram‐positive bacteria to aminoglycoside antibiotics (AGs). After AIEgen‐based treatment, bacteria enter a state of enhanced susceptibility to AGs, characterized by longevity and heritability, offering innovative insights into antibiotic sensitization.