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bioRxiv · 10.1101/2023.09.26.559460

Quinoclamine inhibits Shiga toxin production in enterohemorrhagic Escherichia coli

Kar, O.·Feng, H.-C.·Hirano, H.·Teng, C.-H.·Osada, H.·Hashimoto, M.
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Abstract

ObjectivesEnterohemorrhagic Escherichia coli (EHEC) is responsible for the most severe symptoms of E. coli infections, including hemorrhagic colitis and hemorrhagic uremic syndrome. Shiga toxin 2 (Stx2) plays a significant role as a major virulence factor. The genes encoding Stx2 locate in lambda-like prophage on the EHEC genome. Consequently, Stx2 is expressed when production of the phage is induced by the SOS response. Antibiotic treatment is not recommended for curing the bacterial infection, because it is associated with severe hemorrhagic uremic syndrome. If Stx2 production is prevented, EHEC pathogenicity significantly decreases, and antibiotics may be available to treat the infection. MethodsWe conducted two independent screenings to identify Stx2 production inhibitors for libraries from the RIKEN Natural Product Depository (NPDepo); namely, screening of the Authentic Library, and two-round screening of the Pilot and Analog Libraries. ResultsThe screening of Authentic Library identified niclosamide as a Stx2 production inhibitor. Besides, two naphthoquinoids were identified after the two-round of screening of the Pilot and Analog Libraries. Niclosamide, and quinoclamine, which has structure shared in the two naphthoquinoids, prevented cell lysis via the phage production and ceased Stx2 production in EHEC. The SOS reporter assay indicated that quinoclamine prevented the SOS response in E. coli, whereas niclosamide did not. ConclusionsThese findings suggest that quinoclamine inhibited Stx2 production by preventing the SOS response, whereas niclosamide was involved in phage propagation following the SOS response. These compounds can be a potential therapeutic option to treat EHEC infections.

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Kar, O., Feng, H.-C., Hirano, H., Teng, C.-H., Osada, H., Hashimoto, M.. 2023-09-26. Quinoclamine inhibits Shiga toxin production in enterohemorrhagic Escherichia coli. https://doi.org/10.1101/2023.09.26.559460

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