Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortaseA

被引:61
作者
Song, Meng [1 ,2 ]
Teng, Zihao [1 ,2 ]
Li, Meng [1 ,2 ]
Niu, Xiaodi [1 ,2 ]
Wang, Jianfeng [1 ,2 ]
Deng, Xuming [1 ]
机构
[1] Jilin Univ, Hosp & Inst Infect & Immun 1, Changchun, Jilin, Peoples R China
[2] Jilin Univ, Coll Vet Med, Key Lab Zoonosis, Minist Educ, Changchun, Jilin, Peoples R China
关键词
Streptococcus pneumoniae; pneumolysin; sortase A; neuraminidases A; antivirulence; epigallocatechin gallate; STAPHYLOCOCCUS-AUREUS; SURFACE-PROTEINS; LISTERIA-MONOCYTOGENES; SRTA GENE; CELL-WALL; NASOPHARYNGEAL COLONIZATION; PNEUMOCOCCAL PNEUMONIA; CYTOLYTIC ACTIVITY; BIOFILM FORMATION; EPITHELIAL-CELLS;
D O I
10.1111/jcmm.13179
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Streptococcus pneumoniae (pneumococcus), the causative agent of several human diseases, possesses numerous virulence factors associated with pneumococcal infection and pathogenesis. Pneumolysin (PLY), an important virulence factor, is a member of the cholesterol-dependent cytolysin family and has cytolytic activity. Sortase A (SrtA), another crucial pneumococcal virulence determinate, contributes greatly to the anchoring of many virulence-associated surface proteins to the cell wall. In this study, epigallocatechin gallate (EGCG), a natural compound with little known antipneu-mococcal activity, was shown to directly inhibit PLY-mediated haemolysis and cytolysis by blocking the oligomerization of PLY and simultaneously reduce the peptidase activity of SrtA. The biofilm formation, production of neuraminidase A (NanA, the pneumococcal surface protein anchored by SrtA), and bacterial adhesion to human epithelial cells (Hep2) were inhibited effectively when S. pneumoniae D39 was cocultured with EGCG. The results from molecular dynamics simulations and mutational analysis confirmed the interaction of EGCG with PLY and SrtA, and EGCG binds to Glu277, Tyr358, and Arg359 in PLY and Thr169, Lys171, and Phe239 in SrtA. In vivo studies further demonstrated that EGCG protected mice against S. pneumoniae pneumonia. Our results imply that EGCG is an effective inhibitor of both PLY and SrtA and that an antivirulence strategy that directly targets PLY and SrtA using EGCG is a promising therapeutic option for S. pneumoniae pneumonia.
引用
收藏
页码:2586 / 2598
页数:13
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