Isofagomine inhibits multiple TcdB variants and protects mice fromClostridioides difficileinduced mortality

Abstract

AbstractClostridioides difficilecauses life-threatening diarrhea and is the leading cause of healthcare associated bacterial infections in the United States. During infection,C. difficilereleases 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 infectiveC. difficilecontinue 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 againstC. difficileinduced mortality in two murine models ofC. difficileinfection. Isofagomine treatment of mouseC. difficileinfection permitted recovery of the gastrointestinal microbiota, an important barrier to prevent recurringC. difficileinfection. The broad specificity of isofagomine supports its potential as a prophylactic to protect againstC. difficileinduced morbidity and mortality.