iScience (Jul 2022)

C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus

  • Yu Wu,
  • Nassim Mahtal,
  • Eléa Paillares,
  • Léa Swistak,
  • Sara Sagadiev,
  • Mridu Acharya,
  • Caroline Demeret,
  • Sylvie Van Der Werf,
  • Florence Guivel-Benhassine,
  • Olivier Schwartz,
  • Serena Petracchini,
  • Amel Mettouchi,
  • Lucie Caramelle,
  • Pierre Couvineau,
  • Robert Thai,
  • Peggy Barbe,
  • Mathilde Keck,
  • Priscille Brodin,
  • Arnaud Machelart,
  • Valentin Sencio,
  • François Trottein,
  • Martin Sachse,
  • Gaëtan Chicanne,
  • Bernard Payrastre,
  • Florian Ville,
  • Victor Kreis,
  • Michel-Robert Popoff,
  • Ludger Johannes,
  • Jean-Christophe Cintrat,
  • Julien Barbier,
  • Daniel Gillet,
  • Emmanuel Lemichez

Journal volume & issue
Vol. 25, no. 7
p. 104537

Abstract

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Summary: The development of anti-infectives against a large range of AB-like toxin-producing bacteria includes the identification of compounds disrupting toxin transport through both the endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of compounds blocking Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, which was followed by orthogonal screens against two toxins that hijack the endolysosomal (diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule C910 that induces the enlargement of EEA1-positive early endosomes associated with sorting defects of CNF1 and Shiga toxins to their trafficking pathways. C910 protects cells against eight bacterial AB toxins and the CNF1-mediated pathogenic Escherichia coli invasion. Interestingly, C910 reduces influenza A H1N1 and SARS-CoV-2 viral infection in vitro. Moreover, parenteral administration of C910 to mice resulted in its accumulation in lung tissues and a reduction in lethal influenza infection.

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