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Isofagomine inhibits multiple TcdB variants and protects mice from Clostridioides difficile induced mortality.

ABSTRACT: Clostridioides difficile causes life-threatening diarrhea and is the leading cause of healthcare associated bacterial infections in the United States. During infection, C. difficile releases the gut-damaging toxins, TcdA and TcdB, the primary determinants of disease pathogenesis and are therefore therapeutic targets. TcdA and TcdB contain a glycosyltransferase domain that uses UDP-glucose to glycosylate host Rho GTPases, causing cytoskeletal changes that result in a loss of intestinal integrity. Isofagomine inhibits TcdA and TcdB as a mimic of the oxocarbenium ion transition state of the glycosyltransferase reaction. However, sequence variants of TcdA and TcdB across the clades of infective C. difficile continue to be identified and therefore, evaluation of isofagomine inhibition against multiple toxin variants are required. Here we show that Isofagomine inhibits the glycosyltransferase activity of multiple TcdB variants and also protects TcdB toxin-induced cell rounding of the most common full-length toxin variants. Further, isofagomine protects against C. difficile induced mortality in two murine models of C. difficile infection. Isofagomine treatment of mouse C. difficile infection permitted recovery of the gastrointestinal microbiota, an important barrier to prevent recurring C. difficile infection. The broad specificity of isofagomine supports its potential as a prophylactic to protect against C. difficile induced morbidity and mortality.

SUBMITTER: Paparella AS

PROVIDER: S-EPMC10541099 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Isofagomine inhibits multiple TcdB variants and protects mice from Clostridioides difficile induced mortality.

Paparella Ashleigh S AS Brew Isabella I Hong Huynh A HA Ferriera William W Cutting Simon S Lamiable-Oulaidi Farah F Popadynec Michael M Tyler Peter C PC Schramm Vern L VL

bioRxiv : the preprint server for biology 20230919

Clostridioides difficile causes life-threatening diarrhea and is the leading cause of healthcare associated bacterial infections in the United States. During infection, C. difficile releases the gut-damaging toxins, TcdA and TcdB, the primary determinants of disease pathogenesis and are therefore therapeutic targets. TcdA and TcdB contain a glycosyltransferase domain that uses UDP-glucose to glycosylate host Rho GTPases, causing cytoskeletal changes that result in a loss of intesti ...[more]

PMID: 37781587

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Project description:The dreaded nosocomial pathogen Clostridioides difficile causes diarrhea and severe inflammation of the colon, especially after the use of certain antibiotics. The bacterium releases two deleterious toxins, TcdA and TcdB, into the gut, which are mainly responsible for the symptoms of C. difficile-associated diseases (CDADs). Both toxins are capable of entering independently into various host cells, e.g., intestinal epithelial cells, where they mono-O-glucosylate and inactivate Rho and/or Ras GTPases, important molecular switches for various cellular functions. We have shown recently that the cellular uptake of the Clostridioides difficile toxins TcdA and TcdB (TcdA/B) is inhibited by the licensed class III antiarrhythmic drug amiodarone (Schumacher et al. in Gut Microbes 15(2):2256695, 2023). Mechanistically, amiodarone delays the cellular uptake of both toxins into target cells most likely by lowering membrane cholesterol levels and by interfering with membrane insertion and/or pore formation of TcdA/B. However, serious side effects, such as thyroid dysfunction and severe pulmonary fibrosis, limit the clinical use of amiodarone in patients with C. difficile infection (CDI). For that reason, we aimed to test whether dronedarone, an amiodarone derivative with a more favorable side effect profile, is also capable of inhibiting TcdA/B. To this end, we tested in vitro with various methods the impact of dronedarone on the intoxication of Vero and CaCo-2 cells with TcdA/B. Importantly, preincubation of both cell lines with dronedarone for 1 h at concentrations in the low micromolar range rendered the cells less sensitive toward TcdA/B-induced Rac1 glucosylation, collapse of the actin cytoskeleton, cell rounding, and cytopathic effects, respectively. Our study points toward the possibility of repurposing the already approved drug dronedarone as the preferable safer-to-use alternative to amiodarone for inhibiting TcdA/B in the (supportive) therapy of CDADs.

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Isofagomine inhibits multiple TcdB variants and protects mice from Clostridioides difficile induced mortality.

Publications

Isofagomine inhibits multiple TcdB variants and protects mice from <i>Clostridioides difficile</i> induced mortality.

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