A multitarget ruthenium-clotrimazole complex eradicates MRSA through membrane disruption, DNA intercalation, and ROS generation.

The escalating crisis of antibiotic resistance necessitates the development of agents with novel mechanisms. In this work, three novel ruthenium(II) complexes coordinated with imidazole-based ligands were reported. Among them, Ru-ctz demonstrated exceptional activity against methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) of 0.78 μM, greatly surpassing clotrimazole (MIC = 50 μM), and exceeding both vancomycin (MIC = 1.56 μM) and daptomycin (MIC = 3.12 μM). Mechanistic investigations revealed a synergistic multitarget action: Ru-ctz disrupts bacterial membrane integrity, induces lethal reactive oxygen species (ROS), and intercalates into genomic DNA. It also potently inhibits and eradicates biofilms while suppressing the virulence factor α-hemolysin. Notably, Ru-ctz demonstrated a minimal propensity for resistance development over 20 serial passages. Furthermore, in a murine MRSA skin infection model, Ru-ctz effectively accelerated wound healing and mitigated inflammation, showing good biocompatibility. With its multitarget mechanism, compelling in vitro and in vivo efficacy, and low resistance propensity, Ru-ctz is positioned as a promising therapeutic candidate for combating multidrug-resistant bacterial infections.