Charge Engineering of Star‐Shaped Organic Photosensitizers Enables Efficient Type‐I Radicals for Photodynamic Therapy of Multidrug‐Resistant Bacterial Infection

Abstract Infection induced by multidrug‐resistant bacteria is now the second most common cause of accidental death worldwide. However, identifying a high‐performance strategy with good efficiency and low toxicity is still urgently needed. Antibacterial photodynamic therapy (PDT) is considered a non‐invasive and efficient approach with minimal drug resistance. Whereas, the precise molecular design for highly efficient oxygen‐independent type‐I photosensitizers is still undefined. In this work, the regulation of the positive charge of star‐shaped NIR‐emissive organic photosensitizers can boost radical generation for the efficient treatment of wounds infected with multidrug‐resistant bacteria. With positive charge engineering, TPAT‐DNN, which has six positive charges, mainly produces hydroxyl radicals via the type‐I pathway, while TPAT‐DN, which has three positive charges, tends to generate singlet oxygen and superoxide radicals. For multidrug‐resistant bacteria, TPAT‐DNN exhibited specific killing effects on multidrug‐resistant gram‐positive bacteria at low concentrations, while TPAT‐DN is similar antibacterial effects on both multidrug‐resistant gram‐negative and gram‐positive bacteria. Furthermore, the efficiency and safety of TPAT‐DNN for eradicating multidrug‐resistant bacteria methicillin‐resistant S. aureus (MRSA) infection and accelerating wound healing in an MRSA‐infected mouse model are demonstrated. This work offers a new approach toward manipulating efficient type‐I photosensitizers for MRSA treatment.