Attenuating Listeria monocytogenes virulence by targeting the regulatory protein PrfAShow others and affiliations
2016 (English)In: Cell chemical biology, ISSN 2451-9448, Vol. 23, no 3, p. 404-414Article in journal (Refereed) Published
Abstract [en]
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 infectivity by reducing the expression of virulence genes, without compromising bacterial growth. 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 within a hydrophobic pocket, located between the C- and N-terminal domains of PrfA, and interacts with residues important for PrfA activation. This indicates that these inhibitors maintain the DNA-binding helix-turn-helix motif of PrfA in a disordered state, thereby preventing a PrfA:DNA interaction. Ring-fused 2-pyridones represent a new class of chemical probes for studying virulence in L. monocytogenes.
Place, publisher, year, edition, pages
2016. Vol. 23, no 3, p. 404-414
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-114083DOI: 10.1016/j.chembiol.2016.02.013ISI: 000381508300013PubMedID: 26991105Scopus ID: 2-s2.0-84965007466OAI: oai:DiVA.org:umu-114083DiVA, id: diva2:893601
Note
Originally published in manuscipt form in thesis.
2016-01-122016-01-122023-08-25Bibliographically approved
In thesis