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)](PF6 )2 (Ru(II)-1), [Ru(dtb)2 (MHIP)](PF6 )2 (Ru(II)-2), [Ru(dmb)2 (MHIP)](PF6 )2 (Ru(II)-3), and [Ru(dmob)2 (MHIP)](PF6 )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)-1H-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.