Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A.
Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A.
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表没食子儿茶素没食子酸酯通过同时靶向肺炎链球菌溶血素和分选酶 A 抑制肺炎链球菌毒力
DOI：
10.1111/jcmm.13179
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发表时间：
2017-10
影响因子：
5.3
通讯作者：
Deng X
中科院分区：
文献类型：
--
作者：
Song M;Teng Z;Li M;Niu X;Wang J;Deng X
肺炎链球菌是人类多种疾病的病原体，具有许多与肺炎球菌感染和发病相关的毒力因子。溶血素（acetylolysin，acetylolysin，acetylolysin）是一种重要的毒力因子，属于胆固醇依赖性溶细胞素家族，具有溶细胞活性。分选酶A（SrtA）是另一种关键的肺炎球菌毒力决定因子，它极大地促进了许多毒力相关表面蛋白与细胞壁的锚定。在这项研究中，表没食子儿茶素没食子酸酯（EGCG），一种具有鲜为人知的抗肺炎球菌活性的天然化合物，被证明可以通过阻断SrtA的寡聚化直接抑制SrtA介导的溶血和细胞溶解，同时降低SrtA的肽酶活性。当肺炎链球菌D39与EGCG共培养时，生物膜形成、神经氨酸酶A（NanA，由SrtA锚定的肺炎球菌表面蛋白）的产生以及细菌对人上皮细胞（Hep2）的粘附被有效地抑制。分子动力学模拟和突变分析结果证实了EGCG与cDNAs和SrtA的相互作用，EGCG与cDNAs中的Glu277、Tyr358和Arg359结合，与SrtA中的Thr169、Lys171和Phe239结合。体内研究进一步证明，EGCG保护小鼠免受肺炎链球菌肺炎。我们的研究结果表明，表没食子儿茶素没食子酸酯是一种有效的抑制剂，同时SrtA和直接针对SrtA使用表没食子儿茶素没食子酸酯的抗毒力策略是一个有前途的治疗选择肺炎链球菌肺炎。
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 antipneumococcal 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.
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影响因子：
6.7
作者：
Alhamdi Y;Neill DR;Abrams ST;Malak HA;Yahya R;Barrett-Jolley R;Wang G;Kadioglu A;Toh CH
通讯作者：
Toh CH
影响因子：
6.4
作者：
Blanchette-Cain K;Hinojosa CA;Akula Suresh Babu R;Lizcano A;Gonzalez-Juarbe N;Munoz-Almagro C;Sanchez CJ;Bergman MA;Orihuela CJ
通讯作者：
Orihuela CJ
影响因子：
2.6
作者：
Huang, Ping;Hu, Ping;Chen, Wei Min
通讯作者：
Chen, Wei Min
影响因子：
3.1
作者：
BERRY, AM;YOTHER, J;PATON, JC
通讯作者：
PATON, JC
影响因子：
2.6
作者：
Hotomi, Muneki;Yuasa, Jun;Yamanaka, Noboru
通讯作者：
Yamanaka, Noboru