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 3 404-414Subject Categories
Biochemistry and Molecular Biology
DOI
10.1016/j.chembiol.2016.02.013
PubMed
26991105