1. C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus
- Author
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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, and Emmanuel Lemichez
- Subjects
Biological sciences ,Microbiology ,Science - Abstract
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.
- Published
- 2022
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