Attenuating Listeria Monocytogenes Virulence by Targeting the Regulatory Protein PrfA

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2016 Mar 19

PMID 26991105

Citations 18

Authors

James A D Good

Christopher Andersson

Sabine Hansen

Jessica Wall

K Syam Krishnan

Afshan Begum

Christin Grundstrom

Moritz S Niemiec

Karolis Vaitkevicius

Erik Chorell

Pernilla Wittung-Stafshede

Uwe H Sauer

A Elisabeth Sauer-Eriksson

Fredrik Almqvist

Jorgen Johansson

Affiliations

Soon will be listed here.

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.

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