Synthesis of Innovative Photosensitizers for Enhanced Photodynamic Therapy of Drug-Resistant Pathogens and Biofilms.

Antimicrobial photodynamic therapy (aPDT) has emerged as a potential approach to combating infections triggered by drug-resistant bacteria. However, the selection of photosensitizers for aPDT remains restricted, highlighting the urgent need to develop novel and efficient photosensitizers. Questiomycin A (QA) has garnered attention due to its diverse biomedical activities and good biocompatibility. However, the photodynamic effects of QA and its derivatives have not been explored. Investigating the photodynamic activities of QA-based compounds can provide innovative molecular structures for photosensitizer development. Herein, five derivatives (C1, C2, C3, C4, and C5) of QA are synthesized, and the aPDT activities of these compounds against methicillin-resistant Staphylococcus aureus (MRSA) are assessed. Our findings show that C5- and QA-mediated aPDT exhibits notable bactericidal efficacy, which is better than that of the well-known photosensitizer methylene blue. Especially C5 overcomes the drawbacks associated with the excitation of QA by blue-violet light, such as DNA damage and poor tissue penetration. Mechanism analyses reveal that C5-aPDT can induce singlet oxygen (¹O₂) generation to disrupt bacterial structures and functions, as well as eradicate biofilms and MRSA within biofilms. Studies in the mouse infection model indicate that C5-aPDT markedly promotes wound healing and exhibits excellent biocompatibility with a hemolysis rate of only 0.59% and minimal cell viability inhibition (2.96%) at therapeutic concentrations. To our knowledge, this is the first report that QA derivatives possess outstanding photodynamic activities, providing a unique molecular structure for the design of photosensitizers.