Citation

4165 total record number 127 records this year

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

Wu, Y;Mahtal, N;Paillares, E;Swistak, L;Sagadiev, S;Acharya, M;Demeret, C;Werf, SV;Guivel-Benhassine, F;Schwartz, O;Petracchini, S;Mettouchi, A;Caramelle, L;Couvineau, P;Thai, R;Barbe, P;Keck, M;Brodin, P;Machelart, A;Sencio, V;Trottein, F;Sachse, M;Chicanne, G;Payrastre, B;Ville, F;Kreis, V;Popoff, MR;Johannes, L;Cintrat, JC;Barbier, J;Gillet, D;Lemichez, E;

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.