The Biochemical Mechanisms of Antimicrobial Photodynamic Therapy1

The unbridled dissemination of multidrug-resistant pathogens is a major threat to global health and urgently demands novel therapeutic alternatives. Antimicrobial photodynamic therapy (aPDT) has been developed as a promising approach to treat localized infections regardless of drug resistance profile or taxonomy. Even though this technique has been known for more than a century, discussions and speculations regarding the biochemical mechanisms of microbial inactivation have never reached a consensus on what is the primary cause of cell death. Since photochemically generated oxidants promote ubiquitous reactions with various biomolecules, researchers simply assumed that all cellular structures are equally damaged. In this study, biochemical, molecular, biological and advanced microscopy techniques were employed to investigate whether protein, membrane or DNA damage correlates better with dose-dependent microbial inactivation kinetics. We showed that although mild membrane permeabilization and late DNA damage occur, no correlation with inactivation kinetics was found. On the other hand, protein degradation was analyzed by three different methods and showed a dose-dependent trend that matches microbial inactivation kinetics. Our results provide a deeper mechanistic understanding of aPDT that can guide the scientific community toward the development of optimized photosensitizing drugs and also rationally propose synergistic combinations with antimicrobial chemotherapy.

Automated summary

The uncontrolled spread of multidrug-resistant pathogens is a major global health threat. Antimicrobial photodynamic therapy (aPDT) offers a promising approach to treating localized infections without being limited by drug resistance. In this study, various techniques were used to investigate the biochemical mechanisms of aPDT. The results suggest that protein degradation correlates with microbial inactivation kinetics, providing important insights for the development of optimized photosensitizing drugs and combination therapies with antimicrobial chemotherapy.