Ruthenium complexes as potent antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) via membrane damage.

Abstract

With the growing crisis of multidrug-resistant bacterial infections, a series of novel ruthenium complexes were rationally designed and synthesized to disrupt the integrity of bacterial membranes. In vitro antibacterial screening demonstrated that the lead compound Ru-6 possesses potent bactericidal activity against multiple methicillin-resistant Staphylococcus aureus (MRSA) isolates, with minimum inhibitory concentrations (MICs) ranging from 1.56 to 6.25 μg/mL. Concurrently, Ru-6 displayed negligible hemolytic toxicity toward rabbit erythrocytes. Mechanistic studies suggest that Ru-6 exerts its antibacterial effects through a dual-pathway mechanism: phosphatidylglycerol (PG) acts as a potential membrane interaction partner for Ru-6, facilitating bacterial membrane damage; and also Ru-6 treatment triggers elevated reactive oxygen species (ROS) levels, which is speculated to mediate subsequent intracellular injury. Transcriptomic analysis further revealed that Ru-6 modulates the regulation of bacterial internal genes. In vivo experiments (mouse skin wound infection and Galleria mellonella infection models) confirmed that Ru-6 effectively eradicates MRSA without significant toxicity to host tissues. Ru-6 exhibits considerable potential as a novel antimicrobial agent for clinical application.