Water-Soluble Ruthenium(II) p-Cymene Complexes Mitigating Intracellular S. aureus Infection: Bridging Antibacterial...

The global rise of antimicrobial resistance and aggressive cancers like triple-negative breast cancer (TNBC) demands dual-functional therapies. We synthesized water-soluble ruthenium(II) p-cymene complexes (RuL1-RuL5) using quinoxaline-pyridyl ligands with strategic C6-substitutions. Structure-activity relationship studies identified halogenated RuL1 (-Br) as the most potent, showing selective activity against Gram-positive bacteria (MIC = 8 μg/mL vs Staphylococcus aureus). Mechanistic studies revealed membrane-targeted antibacterial action, supported by AFM, SEM, and fluorescence assays showing disruption, depolarization, and biofilm inhibition. RuL1 was also effective against intracellular S. aureus in HeLa cells, with good hemocompatibility and in vivo efficacy in a murine abscess model. Additionally, RuL1 exhibited strong anticancer activity against MDA-MB-231 TNBC cells (IC₅₀ = ∼2.38 μM), while sparing HEK-293 cells. Mechanistic assays confirmed mitochondrial depolarization, ROS generation, and inhibition of migration and clonal expansion. These results position RuL1 as a promising dual-action metallotherapeutic for combating both drug-resistant bacteria and TNBC.