Fisetin inhibits Listeria monocytogenes virulence by interfering with the oligomerization of listeriolysin O

J Infect Dis. 2015 May 1;211(9):1376-87. doi: 10.1093/infdis/jiu520. Epub 2014 Sep 17.

Abstract

Listeriolysin O (LLO), an essential virulence determinant of Listeria monocytogenes, is a pore-forming toxin whose primary function is to facilitate cytosolic bacterial replication by breaching the phagosomal membranes, which is critical for the pathogen to evade host immune recognition. The critical role of LLO in the virulence of L. monocytogenes renders it an ideal target for designing novel antivirulence therapeutics. We found that fisetin, a natural flavonoid without antimicrobial activity, is a potent antagonist of LLO-mediated hemolysis. Fisetin effectively inhibits L. monocytogenes infection in both tissue culture and animal infection models. Molecular modeling and mutational analysis revealed that fisetin directly engages loop 2 and loop 3 of LLO, leading to the blockage of cholesterol binding and the reduction of its oligomerization, thus inhibiting its hemolytic activity. Our results establish fisetin as an effective antitoxin agent for LLO, which can be further developed into novel therapeutics against infections caused by L. monocytogenes.

Keywords: anti-virulence; infection; molecular modeling; toxin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism*
  • Female
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Gene Expression Regulation, Bacterial / drug effects*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Hemolysin Proteins / genetics
  • Hemolysin Proteins / metabolism*
  • Listeria monocytogenes / drug effects*
  • Listeria monocytogenes / metabolism
  • Listeria monocytogenes / pathogenicity*
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Virulence

Substances

  • Bacterial Toxins
  • Flavonoids
  • Heat-Shock Proteins
  • Hemolysin Proteins
  • fisetin
  • hlyA protein, Listeria monocytogenes