Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA
Journal article, 2016

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.

Author

James A D Good

Umeå University

Christopher Andersson

Umeå University

Sabine Hansen

Umeå University

Jessica Wall

Umeå University

K.S. Krishnan

Umeå University

Mannam Memorial NSS College

Afshan Begum

Umeå University

Christin Grundström

Umeå University

Moritz S. Niemiec

Umeå University

Karolis Vaitkevicius

Umeå University

E. Chorell

Umeå University

Pernilla Wittung Stafshede

Chalmers, Biology and Biological Engineering, Chemical Biology

Uwe H. Sauer

Umeå University

A. Elisabeth Sauer-Eriksson

Umeå University

F. Almqvist

Umeå University

Jörgen Johansson

Umeå University

Cell Chemical Biology

2451-9448 (ISSN) 2451-9456 (eISSN)

Vol. 23 3 404-414

Subject Categories

Biochemistry and Molecular Biology

DOI

10.1016/j.chembiol.2016.02.013

PubMed

26991105

More information

Latest update

2/27/2018