Self-assembled ruthenium(II) nanostructures disrupt electron transport and energy metabolism in MRSA via bacterial interfacial interactions.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has substantially compromised the effectiveness of conventional antibiotic therapies, highlighting the need for alternative antibacterial strategies. Herein, we designed an amphiphilic ruthenium(II) complex(Ru1) that spontaneously self-assembles into highly cationic nanostructures in aqueous media. Molecular dynamics simulations revealed that hydrophobic interactions among long alkyl chains and van der Waals interactions contribute significantly to the self-assembly process. The resulting cationic nanostructures preferentially interact with LTA-rich MRSA cell-envelope interfaces through electrostatic interactions, leading to membrane potential disruption, electron transport chain dysfunction, NAD+/NADH imbalance, and reduced ATP production, ultimately causing bacterial energy metabolic dysfunction. Ru1 exhibited potent antibacterial and antibiofilm activities against MRSA. Furthermore, Ru1 effectively reduced bacterial burden in murine wound and systemic infection models while maintaining favorable biocompatibility. This study provides insights into the role of amphiphilic molecular design and self-assembled interfaces in regulating bacterial interactions and antibacterial activity of Ru(II)-based nanostructures.