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

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. © 2024 Wiley-VCH GmbH.