Targeting bacterial efflux pump effectively enhances the efficacy of Ru-based antibacterial agents against Gram-negative pathogen.

The rise of antibiotic resistance has posed a great threat to human's life, thus develop novel antibacterial agents is urgently needed. It worthies to noted that Ru-based antibacterial agents often showed robust potency against Gram-positive pathogens, disrupted bacterial membrane and avoided bacterial resistance, making they promising antibiotic candidates. However, they are generally less active when applied to negative pathogens. To address this problem, a Ru-based metalloantibiotic (RuN) modified with a nitrothiophene moiety, which can target bacterial efflux pump, was designed and evaluated in this work. A series of assays demonstrated that RuN not only fully retained the advantages of Ru-based agents, such as destroyed bacterial membrane and induced reactive oxygen species production, but also can targeted bacterial efflux pumps. Of course, these properties make it effective in killing both Gram-positive and negative pathogens, its MIC values against Staphylococcus aureus and Escherichia coli lies at 3.125 and 6.25 μg/mL, respectively. Importantly, RuN also showed low toxicity and has robust anti-infective potency in two animal infection models. Together, our results paved an alternative way to enhance the anti-infective efficacy of Ru-based agents against resistant negative bacteria.