Multi-target antibacterial mechanism of ruthenium polypyridine complexes with anthraquinone groups against Staphylococcus aureus

Abstract

Three new Ru(II) complexes, [Ru(dtb)₂PPAD](PF₆)₂ (Ru-1), [Ru(dmob)₂PPAD](PF₆)₂ (Ru-2) and [Ru(bpy)₂PPAD](PF₆)₂ (Ru-3) (dtb = 4,4′-di-tert-butyl-2,2′-bipyridine, dmob = 4,4′-dimethyl-2,2′-bipyridine, bpy = 2,2′-bipyridine and PPAD = 2-(pyridine-3-yl)-1H-imidazo[4,5f][1.10]phenanthracene-9,10-dione), were synthesized and characterized by ¹H NMR and ¹³C NMR spectroscopy, HRMS and HPLC. Among them, Ru-1 showed excellent antimicrobial activity against Gram-positive bacteria Staphylococcus aureus (minimum inhibitory concentration (MIC) = 1 μg mL⁻¹) and low hemolytic and cytotoxic activity. In addition, Ru-1 showed obviously rapid bactericidal activity, low resistance rate, bacterial biofilm destroying activity and high biosafety in vivo. Moreover, skin infection models and a mouse model of sepsis indicated that the anti-infective efficacy of Ru-1 was comparable to that of vancomycin. Mechanism exploration results showed that the antibacterial behavior is probably related with targeting of the bacterial cell membrane and inhibiting topoisomerase I.