Design, synthesis, and evaluation of aryl-thioether ruthenium polypyridine complexes: A multi-target antimicrobial agents against gram-positive bacteria

With the increase in bacterial resistance, new antimicrobial agents are urgently need for developing to combat multidrug-resistant pathogens and with low cytotoxicity. In this study, four new ruthenium polypyridine complexes bearing 4-tBu-phenyl sulfide Ru(bpy)2(TBPIP)](PF6)2 (Ru(Ⅱ)-1), Ru(dmb)2(TBPIP)](PF6)2 (Ru(Ⅱ)-2), Ru(dmob)2(TBPIP)](PF6)2 (Ru(Ⅱ)-3) and Ru(dtb)2(TBPIP)](PF6)2 (Ru(Ⅱ)-4) were designed, synthesized and evaluated. Those ruthenium complexes showed strong activity against Staphylococcus aureus (S. aureus) in vitro and in vivo. The Ru(Ⅱ)-1 showed excellent antimicrobial activity against Gram-positive bacteria (MIC = 2.0 μg/mL), poor hemolytic activity (HC50 > 200 μg/mL), and low cytotoxicity to mammalian cells. Ru(Ⅱ)-1 can kill bacteria quickly by destroying the bacterial membranes and avoid developing bacterial cross-resistance. Moreover, antibacterial mechanism studies show that Ru(Ⅱ)-1 destroys the integrity of bacterial cell membrane by permeabilization and depolarization of bacterial cell membrane, and interacts with bacterial DNA to produce a large number of ROS to kill bacteria. Importantly, Ru(Ⅱ)-1 exhibited effective in vivo efficacy in the mouse S. aureus infection model. These results indicated that ruthenium polypyridine complexes modified with 4-tBu-phenyl sulfide had the therapeutic potential as a novel membrane-active antimicrobial to combat Gram-positive bacterial infections.