title: Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A.
abstract: 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.
authors.affiliation: The First Hospital and Institute of Infection and Immunity, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Song
authors.affiliation: The First Hospital and Institute of Infection and Immunity, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Teng
authors.affiliation: The First Hospital and Institute of Infection and Immunity, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: The First Hospital and Institute of Infection and Immunity, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Niu
authors.affiliation: The First Hospital and Institute of Infection and Immunity, Jilin University, Changchun, China.|Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: The First Hospital and Institute of Infection and Immunity, Jilin University, Changchun, China.
authors.forename: Xuming
authors.identifier: 0000-0001-6411-1074
authors.initials: X
authors.lastname: Deng
mesh_terms: D000072283:A549 Cells; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D011018:Pneumonia, Pneumococcal / Q000382:microbiology / Q000517:prevention & control*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D013301:Streptolysins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D002392:Catechin; C045651:epigallocatechin gallate; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases
keywords: 
  Streptococcus pneumoniae
  ; antivirulence; epigallocatechin gallate; neuraminidases A; pneumolysin; sortase A