1. Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes
- Author
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Ingeborg van der Lingen, Afshan Begum, Marie Lindgren, Fredrik Almqvist, Christin Grundström, Kristoffer Brännström, Andrew G. Cairns, Jörgen Johansson, Uwe Sauer, Sabine Hansen, Michael N. Hall, Martina Kulén, and A. Elisabeth Sauer-Eriksson
- Subjects
Models, Molecular ,0301 basic medicine ,Protein Conformation ,Regulator ,Virulence ,Chick Embryo ,medicine.disease_cause ,DNA-binding protein ,Virulence factor ,Microbiology ,03 medical and health sciences ,Bacterial Proteins ,Listeria monocytogenes ,Drug Discovery ,medicine ,Transcriptional regulation ,Animals ,Binding site ,Pathogen ,Chemistry ,Anti-Bacterial Agents ,3. Good health ,030104 developmental biology ,Drug Design ,Molecular Medicine ,Peptide Termination Factors - 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 (AI), 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-AI selective PrfA inhibitors with potent antivirulence properties.
- Published
- 2018