Ruthenium polypyridine complexes with triphenylamine groups as antibacterial agents against Staphylococcus aureus with membrane-disruptive mechanism

Abstract

Due to the emergence and wide spread of methicillin-resistant Staphylococcus aureus, the treatment of this kind of infection becomes more and more difficult. To solve the problem of drug resistance, it is urgent to develop new antibiotics to avoid the most serious situation of no drug available. Three new Ru complexes [Ru (dmob)2PMA] (PF6)2 (Ru-1) [Ru (bpy)2PMA] (PF6)2 (Ru-2) and [Ru (dmb)2PMA] (PF6)2 (Ru-3) (dmob = 4,4′-dimethoxy-2,2′-bipyridine, bpy = 2,2′-bipyridine, dmb = 4,4′-dimethyl-2,2′-bipyridine and PMA = N-(4-(1H-imidazo [4,5-f] [1,10] phenanthrolin-2-yl) -4-methyl-N-(p-tolyl) aniline) were synthesized and characterized by 1H NMR, 13C NMR and HRMS. The detailed molecular structure of Ru-3 was determined by single crystal X-ray diffraction. Their antibacterial activities against Staphylococcus aureus (Staphylococcus aureus) were obvious and Ru-3 showed the best antibacterial effect with the minimum inhibitory concentration value of 4 μg ml−1. Therefore, further study on its biological activity showed that Ru-3 can effectively inhibit the formation of biofilm and destroy cell membrane. In vitro hemolysis test showed that Ru-3 has almost negligible cytotoxicity to mammalian red blood cells. In the toxicity test of wax moth insect model, Ru-3 exhibited low toxicity in vivo. These results, combined with histopathological studies, strongly suggest that Ru-3 was almost non-toxic. In addition, the synergistic effect of Ru-3 with common antibiotics such as ampicillin, chloramphenicol, tetracycline, kanamycin and gentamicin on Staphylococcus aureus was detected by chessboard method. Finally, in vivo results revealed that Ru-3 could obviously promote the wound healing of Staphylococcus aureus infected mice.

Coupling a Virulence-Targeting Moiety with Ru-Based AMP Mimics Efficiently Improved Its Anti-Infective Potency and Therapeutic Index

“…Results from our previous studies showed that Ru-based complexes bearing different organic ligands efficiently killed S. aureus by damaging bacterial membranes, making them promising AMP mimics. − This finding inspired us to integrate the advantages of AMPs and AvAs into a metalloantibiotic based on the Ru complex, by introducing a functional group to target CcpA. Our study began by screening potential molecules that can target CcpA and are suitable for linking into a Ru-based structure.…”

“…Although AMPs and AvAs show great potential, each has some inherent shortcomings. ,− To address their defects, we attempted to combine these two distinct antibacterial properties into a single molecular scaffold in this study. In our preliminary studies, we had designed a dozen different kinds of Ru-based agents with membrane-disruptive mechanism, − aiming to develop AMP mimics. Notably, the Ru complexes containing pyrene, biphenyl, or aryl-thioether groups exhibited robust potency with MIC of 2 μg/mL.…”

“…Indeed, we found that Ru-based agents are another promising AMP mimics for combating S. aureus in our previous work, and they exhibited robust activity in vitro and in vivo . − To further enter into clinical testing, optimizing their selectivity and cytotoxicity to mammalian cells is essential.…”

Morpholine-modified Ru-based agents with multiple antibacterial mechanisms as metalloantibiotic candidates against Staphylococcus aureus infection

“…The morpholine moiety was linked to the Ru-based structure via long-chain alkyl groups and the detailed synthesis routes are shown in Scheme 1B. All the complexes were characterized by 1 H-NMR, 13 C-NMR and HRMS spectroscopy. In addition, their purity was conrmed by HPLC (ESI †).…”

“…[9][10][11] These advantages make Rubased agents modied with a bioactive moiety exhibit robust antibacterial efficacy and effectively prevent bacteria from developing resistance. [12][13][14][15][16] Morpholine is a natural six-membered ring, which has been widely exploited to enhance the potency of numerous bioactive molecules because of its superior physicochemical, biochemical, and metabolic properties. 17 It was reported that the weakly basic N in morpholine could enhance solubility, whereas the oxygen atom forms hydrogen bonding, which enhances its potency against the target protein by establishing hydrophobic interactions.…”