Abstract
Staphylocoagulase (Coa) is a virulence factor of Staphylococcus aureus (S. aureus) that promotes blood coagulation by activating prothrombin to convert fibrinogen to fibrin. Coa plays a crucial role in disease pathogenesis and is a promising target for the treatment of S. aureus infections. Here, we identified that isoquercitrin, a natural flavonol compound, can markedly reduce the activity of Coa at concentrations that have no effect on bacterial growth. Mechanistic studies employing molecular dynamics simulation revealed that isoquercitrin binds to Coa by interacting with Asp-181 and Tyr-188, thereby affecting the binding of Coa to prothrombin. Importantly, in vivo studies showed that isoquercitrin treatment significantly reduced the bacterial burden, pathological damage, and inflammation of lung tissue and improved the percentage of survival of mice infected with S. aureus Newman strain. These data suggest that isoquercitrin is a promising inhibitor of Coa that can be used for the development of therapeutic drugs to combat S. aureus infections.
Key Points • Staphylocoagulase plays a key role in the pathogenesis of S. aureus infection. • We identified that isoquercitrin is a direct inhibitor of staphylocoagulase. • Isoquercitrin treatment can significantly attenuate S. aureus virulence in vivo. |
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This work was supported by the National Key Research and Development Program of China (2018YFD0500300); the National Key Technology R & D Program (No. 2016YFD05013); the Jilin Province Scientific and Technological Development Program (20180520043JH); and the Science Foundation of Jilin Province, China (No. 20180101276JC).
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Dacheng Wang, Tiedong Wang, and Yongxin Luan conceived and designed research. Zeyuan Gao, Panpan Yang, and Li Wang carried out experiments. Haitao Zhang, Lin Wang, and Shisong Jing analyzed data. Zeyuan Gao and Tiedong Wang wrote the manuscript. All authors read and approved the manuscript.
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Gao, Z., Luan, Y., Yang, P. et al. Targeting staphylocoagulase with isoquercitrin protects mice from Staphylococcus aureus–induced pneumonia. Appl Microbiol Biotechnol 104, 3909–3919 (2020). https://doi.org/10.1007/s00253-020-10486-2
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DOI: https://doi.org/10.1007/s00253-020-10486-2