Design and synthesis of quaternary ammonium-functionalized benzimidazole Ru(II) complexes with potential...

The escalating threat of methicillin-resistant Staphylococcus aureus (MRSA) infections poses a serious challenge to global public health, thereby creating an urgent need for the development of potent antibacterial agents with a low tendency to induce resistance. In this study, ten Ru(II) complexes were designed and synthesized by introducing benzimidazolium quaternary ammonium cations. Preliminary activity screening indicated that compound Ru1 exhibited superior antibacterial activity against S. aureus and methicillin-resistant S. aureus (MRSA). Ru1 showed rapid bactericidal kinetics and also exhibits a strong inhibitory effect on bacterial virulence factors (including biofilm and α-hemolysin), which with a low tendency to induce bacterial resistance. Mechanistically, owing to the high cationic charge density, Ru1 specifically targets and binds to phosphatidylglycerol (PG) on the bacterial membrane. This interaction leads to membrane depolarization and increased permeability, resulting in the leakage of intracellular proteins and nucleic acids, accompanied by substantial accumulation of reactive oxygen species (ROS), ultimately causing bacterial death. In addition, Ru1 displayed remarkable stability in complex physiological environments and excellent biocompatibility. In multiple in vivo efficacy models, Ru1 demonstrated superior therapeutic performance compared with vancomycin. Overall, this study illustrated that quaternate of ruthenium (II) complexes was an effective new strategy for combating drug-resistant bacterial infections.