Ruthenium polypyridine complexes containing prenyl groups as antibacterial agents against Staphylococcus aureus through a membrane‐disruption mechanism

Abstract Four new ruthenium polypyridyl complexes with prenyl groups, [Ru(bpy) 2 (MHIP)](PF 6 ) 2 (Ru(II)‐ 1 ), [Ru(dtb) 2 (MHIP)](PF 6 ) 2 (Ru(II)‐ 2 ), [Ru(dmb) 2 (MHIP)](PF 6 ) 2 (Ru(II)‐ 3 ), and [Ru(dmob) 2 (MHIP)](PF 6 ) 2 (Ru(II)‐ 4 ) (bpy = 2,2′‐bipyridine, dtb = 4,4′‐di‐ tert ‐butyl‐2,2′‐bipyridine, dmb = 4,4′‐dimethyl‐2,2′‐bipyridine, dmob = 4,4′‐dimethoxy‐2,2′‐bipyridine, and MHIP = 2‐(2,6‐dimethylhepta‐1,5‐dien‐1‐yl)−1 H ‐imidazo[4, f ][1,10]phenanthroline), were synthesized and characterized. Their antibacterial activities against Staphylococcus aureus were assessed, and the minimum inhibition concentration (MIC) value of Ru(II)‐ 2 against S. aureus was only 0.5 µg/mL, showing the best antibacterial activity among them. S. aureus could be quickly killed by Ru(II)‐ 2 in 30 min and Ru(II)‐ 2 displayed an obvious inhibitive effect on the formation of a biofilm, which was essential to avoid the development of drug‐resistance. Meanwhile, Ru(II)‐ 2 exhibited a stable MIC value against antibiotic‐resistant bacteria. The antibacterial mechanism of Ru(II)‐ 2 was probably related to depolarization of the cell membrane, and a change of permeability was associated with the formation of reactive oxygen species, leading to leakage of nucleic acid and bacterial death. Furthermore, Ru(II)‐ 2 hardly showed toxicity to mammalian cells and the Galleria mellonella worm. Finally, murine infection studies also illustrated that Ru(II)‐ 2 was highly effective against S. aureus in vivo.