2. Academic Validation
  3. Discovery of synthetic small molecules targeting the central regulator of Salmonella pathogenicity

Discovery of synthetic small molecules targeting the central regulator of Salmonella pathogenicity

  • Sci Adv. 2025 Apr 11;11(15):eadr5235. doi: 10.1126/sciadv.adr5235.
Abdelhakim Boudrioua 1 2,  Joe D Joiner 3,  Iwan Grin 1 2,  Thales Kronenberger 2 4 5,  Vadim S Korotkov 6,  Wieland Steinchen 7 8,  Alexander Kohler 1 2,  Sophie Schminke 1,  Julia-Christina Schulte 1 2,  Michael Pietsch 9,  Arun Naini 6,  Simon Kalverkamp 6,  Sven-Kevin Hotop 6,  Travis Coyle 6,  Claudio Piselli 2 3,  Murray Coles 3,  Katharina Rox 6 10,  Matthias Marschal 4,  Gert Bange 7 8,  Antje Flieger 9,  Antti Poso 5 11,  Mark Brönstrup 6 10 12,  Marcus D Hartmann 2 3 13,  Samuel Wagner 1 2 14
Affiliations

Affiliations

  • 1 Section of Cellular and Molecular Microbiology, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Elfriede-Aulhorn-Str. 6, 72076 Tübingen, Germany.
  • 2 German Center for Infection Research (DZIF), partner-site Tübingen, 72076 Tübingen, Germany.
  • 3 Department of Protein Evolution, Max Planck Institute for Biology Tübingen, Tübingen, Germany.
  • 4 Institute of Medical Microbiology and Hygiene, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Elfriede-Aulhorn-Str. 6, 72076 Tübingen, Germany.
  • 5 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • 6 Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
  • 7 Center for Synthetic Microbiology, Philipps University of Marburg, Karl-von-Frisch-Str. 14, 35043 Marburg, Germany.
  • 8 Department of Chemistry, Philipps University of Marburg, Hans Meerwein-Str. 4, 35043 Marburg, Germany.
  • 9 Unit for Enteropathogenic Bacteria and Legionella (FG11) and National Reference Centre for Salmonella and other Bacterial Enterics, Robert Koch Institute (RKI), Burgstr. 37, 38855 Wernigerode, Germany.
  • 10 German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124 Braunschweig, Germany.
  • 11 Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery (TüCAD2), University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 12 Institute of Organic Chemistry and Biomolecular Drug Research Centre (BMWZ), Leibniz University Hannover, Schneiderberg 1B, 30167 Hannover, Germany.
  • 13 Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
  • 14 Excellence Cluster "Controlling Microbes to Fight Infections" (CMFI), Elfriede-Aulhorn-Str. 6, 72076 Tübingen, Germany.
PMID: 40215303 DOI: 10.1126/sciadv.adr5235
Abstract

The enteric pathogen Salmonella enterica serovar Typhimurium relies on the activity of effector proteins to invade, replicate, and disseminate into host epithelial cells and Other tissues, thereby causing disease. Secretion and injection of effector proteins into host cells is mediated by dedicated secretion systems, which hence represent major virulence determinants. Here, we report the identification of a synthetic small molecule with drug-like properties, C26, which suppresses the secretion of effector proteins and consequently hinders Bacterial invasion of eukaryotic cells. C26 binds to and inhibits HilD, the transcriptional regulator of the major secretion systems. Although sharing the same binding pocket as the previously described long-chain fatty acid ligands, C26 inhibits HilD with a unique binding mode and a distinct mechanism. We provide evidence of intramacrophage activity and present analogs with improved potency and suitability as scaffolds to develop antivirulence agents against Salmonella infections in humans and Animals.

Figures
Products