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

The escalating threat of Methicillin-resistant Staphylococcus
aureus (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(DIPPB)] (PF6)3 (Ru-1),
[Ru(II)(dmb)2(DIPPB)] (PF6)3 (Ru-2), [Ru(II)(dmob)2(DIPPB)] (PF6)3 (Ru-3) and [Ru(II)(bpy)2(DIPPB)] (PF6)3 (Ru-4). Among these complexes, complex Ru-4 incorporates N-methylimidazole and quaternary ammonium cations, in vitro
experiments have demonstrated the presence of potent antibacterial
activity against Staphylococcus aureus 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, in vivo experimental results demonstrated
that Ru-4 exhibits superior efficacy compared to vancomycin,
thereby identifying it as a promising therapeutic candidate for MRSA
infection treatment.