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  • 标题:C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus
  • 本地全文:下载
  • 作者:Yu Wu ; Nassim Mahtal ; Eléa Paillares
  • 期刊名称:iScience
  • 印刷版ISSN:2589-0042
  • 出版年度:2022
  • 卷号:25
  • 期号:7
  • 页码:1-27
  • DOI:10.1016/j.isci.2022.104537
  • 语种:English
  • 出版社:Elsevier
  • 摘要:SummaryThe 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 pathogenicEscherichia coliinvasion. Interestingly, C910 reduces influenza A H1N1 and SARS-CoV-2 viral infectionin vitro. Moreover, parenteral administration of C910 to mice resulted in its accumulation in lung tissues and a reduction in lethal influenza infection.Graphical abstractDisplay OmittedHighlights•Screen for inhibitors disrupting bacterial AB toxins vesicular trafficking pathways•C910 affects EEA1/Rab5-positive early endosome morphology and sorting functions•C910 protects cells against eight AB toxins, SARS-CoV-2 and influenza A virus•C910 accumulates in lung tissues and protects mice against influenza A virusBiological sciences; Microbiology
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