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© Emmanuel Lemichez
Microscopy image showing the formation of large tunnels in a blood vessel endothelial cell induced by a group of bacterial toxins
Scientific Fields
Diseases
Organisms
Applications
Technique

Published in iScience - 15 Jul 2022

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,

Link to Pubmed [PMID] – 35769882

Link to DOI – 10.1016/j.isci.2022.104537

iScience 2022 Jul; 25(7): 104537

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.

https://pubmed.ncbi.nlm.nih.gov/35769882