Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA

Cell Chem Biol. 2016 Mar 17;23(3):404-14. doi: 10.1016/j.chembiol.2016.02.013.


The transcriptional activator PrfA, a member of the Crp/Fnr family, controls the expression of some key virulence factors necessary for infection by the human bacterial pathogen Listeria monocytogenes. Phenotypic screening identified ring-fused 2-pyridone molecules that at low micromolar concentrations attenuate L. monocytogenes cellular uptake by reducing the expression of virulence genes. These inhibitors bind the transcriptional regulator PrfA and decrease its affinity for the consensus DNA-binding site. Structural characterization of this interaction revealed that one of the ring-fused 2-pyridones, compound 1, binds at two separate sites on the protein: one within a hydrophobic pocket or tunnel, located between the C- and N-terminal domains of PrfA, and the second in the vicinity of the DNA-binding helix-turn-helix motif. At both sites the compound interacts with residues important for PrfA activation and helix-turn-helix formation. Ring-fused 2-pyridones represent a new class of chemical probes for studying virulence in L. monocytogenes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Binding Sites / drug effects
  • Caco-2 Cells
  • Cell Line
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Listeria monocytogenes / drug effects*
  • Listeria monocytogenes / pathogenicity*
  • Models, Molecular
  • Peptide Termination Factors / genetics
  • Peptide Termination Factors / metabolism*
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Structure-Activity Relationship
  • Virulence / drug effects


  • Bacterial Proteins
  • Peptide Termination Factors
  • PrfA protein, Listeria monocytogenes
  • Pyridones
  • 2-hydroxypyridine