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A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2

A challenge for the development of host-targeted anti-infectives against a large spectrum of AB-like toxin-producing bacteria encompasses the identification of chemical compounds corrupting toxin transport through both endolysosomal and retrograde pathways. Here, we performed a high-throughput scree...

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Published in:bioRxiv 2021-08
Main Authors: Wu, Yu, Mahtal, Nassim, Swistak, Lea, Sagadiev, Sara, Acharya, Mridu, Demeret, Caroline, Van Der Werf, Sylvie, Guivel-Benhassine, Florence, Schwartz, Olivier, Petracchini, Serena, Mettouchi, Amel, Paillares, Elea, Caramelle, Lucie, Couvineau, Pierre, Thai, Robert, Barbe, Peggy, Keck, Mathilde, Brodin, Priscille, Machelart, Arnaud, Sencio, Valentin, Trottein, Francois, Sachse, Martin, Chicanne, Gaetan, Payrastre, Bernard, Ville, Florian, Kreis, Victor, Michel-Robert Popoff, Johannes, Ludger, Jean-Christophe Cintrat, Barbier, Julien, Gillet, Daniel, Lemichez, Emmanuel
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Language:English
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Summary:A challenge for the development of host-targeted anti-infectives against a large spectrum of AB-like toxin-producing bacteria encompasses the identification of chemical compounds corrupting toxin transport through both endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of small chemical compounds blocking active Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, followed by orthogonal screens against two AB toxins hijacking defined endolysosomal (Diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule N-(3,3-diphenylpropyl)-1-propyl-4-piperidinamine, referred to as C910. This compound induces the swelling of EEA1-positive early endosomes, in absence of PIKfyve kinase inhibition, and disturbs the trafficking of CNF1 and the B-subunit of Shiga toxin along the endolysosomal or retrograde pathways, respectively. Together, we show that C910 protects cells against 8 bacterial AB toxins including large clostridial glucosylating toxins from Clostridium difficile. Of interest, C910 also reduced viral infection in vitro including influenza A virus subtype H1N1 and SARS-CoV-2. Moreover, parenteral administration of C910 to the mice resulted in its accumulation in lung tissues and reduced lethal influenza infection. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2021.08.13.454991