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

Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA.

Author information

1
Department of Chemistry, Umeå University, 901 87 Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden.
2
Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden; Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden; Molecular Infection Medicine, Sweden (MIMS), Umeå University, 901 87 Umeå, Sweden.
3
Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
4
Department of Chemistry, Umeå University, 901 87 Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden. Electronic address: elisabeth.sauer-eriksson@umu.se.
5
Department of Chemistry, Umeå University, 901 87 Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden. Electronic address: fredrik.almqvist@umu.se.
6
Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden; Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden; Molecular Infection Medicine, Sweden (MIMS), Umeå University, 901 87 Umeå, Sweden. Electronic address: jorgen.johansson@umu.se.

Abstract

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.

PMID:
26991105
PMCID:
PMC4802734
DOI:
10.1016/j.chembiol.2016.02.013
[Indexed for MEDLINE]
Free PMC Article

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