Design and Synthesis of Membrane-Targeting Poly-Ruthenium Complexes Containing Quaternary Ammonium Cations with Potential Antibacterial Activity against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA)

The escalating threat of Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infections seriously endangers human health, so facing the immense threat of drug-resistant bacteria, discovering new and potent antibacterial drugs less prone to inducing resistance is urgently needed. In this study, four amphiphilic ruthenium polypyridyl complexes were synthesized, namely [Ru(II)(bpy)₂(<b>DIPPB</b>)] (PF₆)₃ (<b>Ru-1</b>), [Ru(II)(dmb)₂(<b>DIPPB</b>)] (PF₆)₃ (<b>Ru-2</b>), [Ru(II)(dmob)₂(<b>DIPPB</b>)] (PF₆)₃ (<b>Ru-3</b>) and [Ru(II)(bpy)₂(<b>DIPPB</b>)] (PF₆)₃ (<b>Ru-4</b>). Among these complexes, complex <b>Ru-4</b> incorporates <i>N</i>-methylimidazole and quaternary ammonium cations, in vitro experiments have demonstrated the presence of potent antibacterial activity against <i>Staphylococcus aureus</i> and MRSA, accompanied by low hemolytic activity and a diminished tendency to induce drug resistance. It acts by disrupting bacterial membranes via interaction with phosphatidylglycerol and phosphatidylethanolamine, increasing permeability, elevating ROS levels, and causing content leakage. Transcriptomics confirmed its impact on membrane-related genes. Notably, <i>in vivo</i> experimental results demonstrated that <b>Ru-4</b> exhibits superior efficacy compared to vancomycin, thereby identifying it as a promising therapeutic candidate for MRSA infection treatment.