Design, synthesis and evaluation of phenyl sulfonyl fluoride substituted ruthenium polypyridine complex as antibacterial agent targeting cell membrane

The emergence of multidrug-resistance bacteria has significantly increased mortality rates and difficulty to treatment. Therefore, it is an urgent need to develop new antimicrobial agents to address this seriously situation. In this study, three functionalized phenyl sulfonyl fluoride polypyridine ruthenium complexes [Ru(bpy)2(PBSOP)](PF6)2 (Ru1), [Ru(dmb)2(PBSOF)](PF6)2 (Ru2), and [Ru(dtb)2(PBSOF)](PF6)2 (Ru3), were synthesized and evaluated their antibacterial activity. Results showed that in vitro the minimum inhibitory concentration (MIC) of Ru3 against S. aureus was only 3.125 µg/mL compared other two compounds. In addition, Ru3 also exhibits low hemolytic activity and good biocompatibility, while inhibiting toxin secretion and biofilm formation. As a result, it restores antibiotic sensitivity and reduces to drug resistance. Interestingly, Ru3 can also target phosphatidylglycerol (PG), an important component of Gram-positive bacterial cell membranes, there by disrupting the integrity of the bacterial cell membrane. Finally, Ru3 also exerted promising therapeutic effects in vivo infection models, with Galleria mellonella larvae showing up to 70% therapeutic efficacy. In the mouse peritonitis model, Ru3 could cure 80% of the mice with a single dose of 20 mg/kg. In the mouse skin infection model, Ru3 still showed excellent therapeutic effect, strong wound healing ability, and no irritation to the mouse skin. In conclusion, those phenyl sulfonyl fluoride ruthenium polypyridine complexes obtained exhibit robust antibacterial activity with satisfactory biocompatibility thus offering enormous potential for antibacterial treatment providing a new perspective on addressing the current global crisis.