Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA
Artikel i vetenskaplig tidskrift, 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.

Författare

James A D Good

Umeå universitet

Christopher Andersson

Umeå universitet

Sabine Hansen

Umeå universitet

Jessica Wall

Umeå universitet

K.S. Krishnan

Umeå universitet

Mannam Memorial NSS College

Afshan Begum

Umeå universitet

Christin Grundström

Umeå universitet

Moritz S. Niemiec

Umeå universitet

Karolis Vaitkevicius

Umeå universitet

E. Chorell

Umeå universitet

Pernilla Wittung Stafshede

Chalmers, Biologi och bioteknik, Kemisk biologi

Uwe H. Sauer

Umeå universitet

A. Elisabeth Sauer-Eriksson

Umeå universitet

F. Almqvist

Umeå universitet

Jörgen Johansson

Umeå universitet

Cell Chemical Biology

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

Vol. 23 404-414

Ämneskategorier

Biokemi och molekylärbiologi

DOI

10.1016/j.chembiol.2016.02.013

PubMed

26991105