Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes

Martina Kulén, Marie Lindgren, Sabine Hansen, Andrew G. Cairns, Christin Grundström, Afshan Begum, Ingeborg Van Der Lingen, Kristoffer Brännström, Michael Hall, Uwe H. Sauer, Jörgen Johansson (Lead / Corresponding author), A. Elisabeth Sauer-Eriksson (Lead / Corresponding author), Fredrik Almqvist (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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 I ), 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 I selective PrfA inhibitors with potent antivirulence properties.

Original languageEnglish
Pages (from-to)4165-4175
Number of pages11
JournalJournal of Medicinal Chemistry
Volume61
Issue number9
Early online date18 Apr 2018
DOIs
Publication statusPublished - 10 May 2018

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