De Novo Design of Multi-Mechanistic AIE Photosensitizer for Broad-Spectrum Bacterial Eradication

Abstract Antibiotic resistance poses a serious threat to human health. Inspired by the clinical practice of employing drug combinations to achieve combined effects, we hypothesized that integrating multiple mechanisms into a single molecule could address drug-resistant bacterial infections. Based on a propeller-modification strategy and dual alkyl-chain engineering, we de novo designed and synthesized a C2-symmetric propeller-shaped aggregation-induced emission photosensitizer. After iterative screening, the optimized compound MeOTDP-2 exhibits broad-spectrum antibacterial activity, enabling efficient eradication of planktonic bacteria, drug-resistant strains, polymicrobial infections, biofilms, and persister cells, with no cellular invasiveness and negligible cytotoxicity. Mechanistic studies revealed that MeOTDP-2 achieves chemo-photodynamic combined antibacterial therapy by targeting and disrupting bacterial membranes and DNA, alongside light-mediated intracellular reactive oxygen species accumulation. Furthermore, in mouse models of MRSA-induced skin abscess and full-thickness skin wound infection, MeOTDP-2 demonstrated superior therapeutic efficacy to vancomycin. This strategy, integrating dual targeting with multiple mechanisms, offers new promise for overcoming bacterial resistance.