Acacetin Protects Mice from Staphylococcus aureus Bloodstream Infection by Inhibiting the Activity of Sortase A.
Staphylococcus aureus(S. aureus) is a major cause of infection in hospitals and communities. Widespread dissemination of multi-drug resistantS. aureusis a serious threat to the health of humans and animals. An anti-virulence strategy has been widely considered as an alternative therapeutic approach. Inhibitors of virulence factors are able to treatS. aureusinfections without influencing the growth or viability of bacteria and rarely lead to bacterial resistance. Sortase A (SrtA) is a membrane-associated cysteine transpeptidase that catalyzes up to 25 surface proteins that covalently bind to cell wall peptidoglycans. InS. aureus, most of these surface proteins have been identified as important virulence factors that are vital in bacterial pathogenesis. In the present study, we show that acacetin, a natural flavonoid compound, inhibits the activity of SrtA inS. aureus(IC50= 36.46 ± 4.69 μg/mL, 128 μM) which affects the assembly of protein A (SpA) to cell walls and reduces the binding ofS. aureusto fibrinogen (Fg). The mechanism of the interaction between acacetin and SrtA were preliminarily discussed using molecular dynamics simulations. The results suggested that acacetin adopted a compact conformation binding at the pocket of the SrtA via residues Arg-139 and Lys-140. By performing an animal infection model, we demonstrated that acacetin was able to protect mice from renal abscess formation induced byS. aureusand significantly increased survival rates. Taken together, these findings suggest that acacetin may be a promising candidate for the development of anti-S. aureusdrugs.
College of Animal Science, Jilin University, Changchun 130062, China. bicwei@gmail.com.
Chongwei
C
Bi
Department of Pharmacology, College of Basic Medical Science, Jilin University, Changchun 130062, China. banyuexiao@126.com.
Xiaoyun
X
Dong
College of Animal Science, Jilin University, Changchun 130062, China. 15043029208@163.com.
Xiaobo
X
Zhong
College of Animal Science and Technology, Jilin Agricultural University, Changchun 130062, China. chj6788571@163.com.
Hongjun
H
Cai
College of Animal Science, Jilin University, Changchun 130062, China. wangdc@jlu.edu.cn.
Dacheng
D
Wang
Key Laboratory of Zoonosis Research, Ministry of Education/Institute of Zoonosis/College of Veterinary Medicine, Jilin University, Changchun 130062, China. wanglin1020@jlu.edu.cn.
Lin
L
Wang
Staphylococcus aureus; acacetin; inhibitor; renal abscess; sortase A
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