Abstract
Staphylococcus aureus is a major human pathogen, and the appearance of methicillin-resistant S. aureus (MRSA) renders S. aureus infections more challenging to treat. Therefore, new antimicrobial drugs are urgently needed to combat MRSA infections. Drug repurposing is an effective and feasible strategy. Here, we reported that the clinically approved anti-hepatitis C virus drug simeprevir had strong antibacterial activity against MRSA, with a minimum inhibitory concentration of 2–8 µg/mL. Simeprevir did not easily induce in vitro resistance. In addition, simeprevir significantly prevented S. aureus biofilm formation. Furthermore, simeprevir displayed limited toxicity in in vitro and in vivo assays. Moreover, simeprevir showed synergistic antimicrobial effects against both type and clinical strains of S. aureus. Simeprevir combined with gentamicin effectively reduced the bacterial burden in an MRSA–infected subcutaneous abscess mouse model. Results from a series of experiments, including membrane permeability assay, membrane potential assay, intracellular ATP level assay, and electron microscope observation, demonstrated that the action of simeprevir may be by disrupting bacterial cell membranes. Collectively, these results demonstrated the potential of simeprevir as an antimicrobial agent for the treatment of MRSA infections.
Key points
• Simeprevir showed strong antibacterial activity against MRSA.
• The antibacterial mechanism of simeprevir was mediated by membrane disruption and intracellular ATP depletion.
• In vitro and in vivo synergistic antimicrobial efficacy between simeprevir and gentamicin was found.
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This work was supported by the National Natural Science Foundation of China, grant number 82072350, and the Natural Science Foundation of Hunan Province, grant number 2021JJ40944.
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YLi and PS contributed equally to this study. PS and YW designed and conceived the experiments. YLi wrote this manuscript and performed most of the experiments. LX and YLiu conducted the supporting experiments. YLi, PS, SL, and ZL analyzed the research data and made data curration and figures. YLi, PS, YY, LL, and ZH prepared study materials, reagents, and analysis tools. PS and YW reviewed and edited the manuscript. PS and YW supervised the entire experimental work. All authors read and approved the final version of the manuscript.
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Li, Y., She, P., Xu, L. et al. Anti-hepatitis C virus drug simeprevir: a promising antimicrobial agent against MRSA. Appl Microbiol Biotechnol 106, 2689–2702 (2022). https://doi.org/10.1007/s00253-022-11878-2
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DOI: https://doi.org/10.1007/s00253-022-11878-2