Corilagin: A Novel Antivirulence Strategy to Alleviate Streptococcus pneumoniae Infection by Diminishing Pneumolysin Oligomers

Abstract

Pneumolysin (PLY) is a significant virulence factor of Streptococcus pneumoniae (S. pneumoniae), able to break through the defense system of a host and mediate the occurrence of a series of infections. Therefore, PLY as the most ideal target to prevent S. pneumoniae infection has received more and more attention and research. Corilagin is a tannic acid that exhibits excellent inhibition of PLY oligomers without bacteriostatic activity to S. pneumoniae. Herein, hemolytic activity assays, cell viability tests and western blot experiments are executed to evaluate the antivirulence efficacy of corilagin against PLY in vitro. Colony observation, hematoxylin and eosin (H&E) staining and cytokines of bronchoalveolar lavage fluid (BALF) are applied to assess the therapeutic effect of corilagin in mice infected by S. pneumoniae. The results indicate the related genes of corilagin act mainly via enrichment in pathways associated with pneumonia disease. Furthermore, molecular docking and molecular dynamics simulations show that corilagin might bind with domains 3 and 4 of PLY and interfere with its hemolytic activity, which is further confirmed by the site-directed mutagenesis of PLY. Additionally, corilagin limits PLY oligomer production without impacting PLY expression in S. pneumoniae cultures. Moreover, corilagin effectively relieves PLY-mediated cell injury without any cytotoxicity, even then reducing the colony count in the lung and the levels of pro-inflammatory factors in BALF and remarkably improving lung lesions. All the results demonstrate that corilagin may be a novel strategy to cope with S. pneumoniae infection by inhibiting PLY oligomerization.