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Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 May 10; Vol. 61 (9), pp. 4165-4175. Date of Electronic Publication: 2018 Apr 27. - Publication Year :
- 2018
-
Abstract
- Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure-guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A <subscript>I</subscript> ), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix-turn-helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A <subscript>I</subscript> selective PrfA inhibitors with potent antivirulence properties.
- Subjects :
- Animals
Bacterial Proteins chemistry
Bacterial Proteins metabolism
Chick Embryo
Listeria monocytogenes pathogenicity
Models, Molecular
Peptide Termination Factors chemistry
Peptide Termination Factors metabolism
Protein Conformation
Virulence drug effects
Anti-Bacterial Agents chemistry
Anti-Bacterial Agents pharmacology
Bacterial Proteins antagonists & inhibitors
Drug Design
Listeria monocytogenes drug effects
Listeria monocytogenes metabolism
Peptide Termination Factors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29667825
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00289