Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A

Virulence

Ying Ding¹  Yajing Jin¹  Shisong Jing¹  Lin Yang¹  Hangqian Yu¹  Dacheng Wang¹  Li Wang¹  Kai Wang²  Han Qu²  Qianxue Li²  Yan Shi³ 

[1] College of Animal Science, Jilin University, Changchun Chin;Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Chin;School of Pharmaceutical Science, Jilin University, Changchun Chin;

关键词: Staphylococcus aureus;    anti-virulence;    orientin;    inhibitor;    Sortase A;    pneumonia;   

DOI  :  10.1080/21505594.2021.1962138

来源: Taylor & Francis

【 摘 要 】

Drug-resistant pathogenic Staphylococcus aureus (S. aureus) has severely threatened human health and arouses widespread concern. Sortase A (SrtA) is an essential virulence factor of S. aureus, which is responsible for the covalent anchoring of a variety of virulence-related proteins to the cell wall. SrtA has always been regarded as an ideal pharmacological target against S. aureus infections. In this research, we have determined that orientin, a natural compound isolated from various medicinal plants, can effectively inhibit the activity of SrtA with an IC50 of 50.44 ± 0.51 µM. We further demonstrated that orientin inhibited the binding of S. aureus to fibrinogen and diminished biofilm formation and the attaching of Staphylococcal protein A (SpA) to the cell wall in vitro. Using the fluorescence quenching assay, we demonstrated a direct interaction between orientin and SrtA. Further mechanistic studies revealed that the residues Glu-105, Thr-93, and Cys-184 were the key sites for the binding of SrtA to orientin. Importantly, we demonstrated that treatment with orientin attenuated S. aureus virulence of in vivo and protected mice against S. aureus-induced lethal pneumonia. These findings indicate that orientin is a potential drug to counter S. aureus infections and limit the development of drug resistance.

【 授权许可】

CC BY