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
Umea universitet
Christopher Andersson
Umea universitet
Sabine Hansen
Umea universitet
Jessica Wall
Umea universitet
K.S. Krishnan
Mannam Memorial NSS College
Umea universitet
Afshan Begum
Umea universitet
Christin Grundström
Umea universitet
Moritz S. Niemiec
Umea universitet
Karolis Vaitkevicius
Umea universitet
E. Chorell
Umea universitet
Pernilla Wittung Stafshede
Chalmers, Biology and Biological Engineering, Chemical Biology
Uwe H. Sauer
Umea universitet
A. Elisabeth Sauer-Eriksson
Umea universitet
F. Almqvist
Umea universitet
Jörgen Johansson
Umea universitet
Cell Chemical Biology
2451-9448 (ISSN) 2451-9456 (eISSN)
Vol. 23 3 404-414Subject Categories (SSIF 2011)
Biochemistry and Molecular Biology
DOI
10.1016/j.chembiol.2016.02.013
PubMed
26991105