Combating Multiple-Drug Resistance Polymicrobial Biofilm Infections with an Amphiphilic Cationic Photosensitizer

Polymicrobial infections, particularly those involving both Gram-positive (G+) and Gram-negative (G−) bacteria, present a severe public health threat due to the lack of effective treatments. The formation of polymicrobial biofilms further complicate this challenge, underscoring the urgent need for innovative therapeutic strategies. To address this issue, we designed a series of amphiphilic cationic photosensitizers (PSs) featuring distinct hydrophilic cationic side chains (pyridinium, imidazolium, alkyl quaternary ammonium, and quaternary phosphonium) and systematically investigated their structure–activity relationships. Among them, the pyridinium-modified PS, TBTCP-PY, demonstrated a superior performance. It efficiently generates hydroxyl radicals (•OH) and singlet oxygen ( 1 O 2 ) upon light irradiation, enabling it to target and disrupt the membranes of both G+ and G– bacteria. Furthermore, TBTCP-PY exhibits a strong capacity to penetrate extracellular polymeric substances (EPS), leading to the effective eradication of polymicrobial biofilms formed by methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDR-PA). In a murine model, TBTCP-PY successfully eliminated MRSA-MDR-PA polymicrobial biofilms from implanted medical catheters, reduced subsequent inflammation, and promoted wound healing. This work not only presents a promising candidate for treating complex polymicrobial biofilm infections but also provides valuable theoretical insights into developing novel antibiofilm materials.