Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes

J Med Chem. 2018 May 10;61(9):4165-4175. doi: 10.1021/acs.jmedchem.8b00289. Epub 2018 Apr 27.

Abstract

Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure-guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (AI), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix-turn-helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-AI selective PrfA inhibitors with potent antivirulence properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Chick Embryo
  • Drug Design*
  • Listeria monocytogenes / drug effects*
  • Listeria monocytogenes / metabolism*
  • Listeria monocytogenes / pathogenicity
  • Models, Molecular
  • Peptide Termination Factors / antagonists & inhibitors*
  • Peptide Termination Factors / chemistry
  • Peptide Termination Factors / metabolism
  • Protein Conformation
  • Virulence / drug effects

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Peptide Termination Factors
  • PrfA protein, Listeria monocytogenes