 |
|
Title
|
|
Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA.
|
|
|
Authors
|
|
J.A.Good,
C.Andersson,
S.Hansen,
J.Wall,
K.S.Krishnan,
A.Begum,
C.Grundström,
M.S.Niemiec,
K.Vaitkevicius,
E.Chorell,
P.Wittung-Stafshede,
U.H.Sauer,
A.E.Sauer-Eriksson,
F.Almqvist,
J.Johansson.
|
|
|
Ref.
|
|
Cell Chem Biol, 2016,
23,
404-414.
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|