Advanced applications of cationic photosensitizer DHPC in photodynamic eradication of drug-resistant bacteria

Photodynamic therapy (PDT) is increasingly viewed as a reliable and effective treatment for infections caused by antibiotic-resistant bacteria. However, the limited uptake of photosensitizers (PS) by bacteria remains a major challenge. Cationization enables PS to accumulate around bacterial cells, thereby promoting their intracellular delivery. In particular, cationic small-molecule PS are characterized by carrier-free bacterial enrichment, efficient biofilm penetration, high stability, straightforward synthesis, and moderate charges that minimize toxicity, making them a sustained focus in antimicrobial PS development. Herein, we investigate the potential of a cationic small-molecule PS, DHPC [(E)-8-(diethylamino)-2-(4-(diethylamino)-2-hydroxystyryl)-4-oxo-4H-pyrano[2,3-b]chromen-10-ium], for combating drug-resistant pathogens. Our results demonstrate that DHPC-mediated PDT (DHPC-PDT) effectively eradicates drug-resistant bacteria, including antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa , with greater efficacy compared to the commonly used photosensitizer methylene blue (MB). Furthermore, DHPC-PDT exhibits superior bactericidal activity compared to antitumor activity, with the two effects involving distinct underlying mechanisms, indicating that DHPC-PDT is better suited for antibacterial applications. It also shows a dual-action efficacy against biofilms, both inhibiting biofilm formation and eradicating mature biofilms. In vivo , DHPC-PDT reduces the bacterial burden in infected wounds, modulates the local inflammatory microenvironment, and accelerates wound healing, with preliminary evidence of favorable biocompatibility. This study presents DHPC as a potential PS for antimicrobial PDT.