A non-antibiotic drug reduces the effects Clostridium difficile infection (CDI) by disabling the bacteria’s toxins, a study showed in mice. The orally administered agent, ebselen, has been in clinical trials for an unrelated condition and could offer a new approach for combating multidrug-resistant CDI.
C difficile infection causes life-threatening diarrhea and colitis, or inflammation of the colon, in more than a quarter million people in the US each year. The disease has been associated with the widespread use of broad-spectrum antibiotics.
Although there are antibiotic treatments for CDI, they can promote drug resistance and prevent healthy microbes from recolonizing the gut. In search of new treatment options, Kristina Oresic Bender et al screened a library of compounds for drugs that targeted C difficile’s toxins.
In the September 23 issue of Science Translational Medicine, Oresic Bender et al report that ebselen targets the cysteine protease domain within the C difficile major virulence factor toxin B (TcdB). This drug showed activity against both major virulence factors, TcdA and TcdB, in biochemical, cellular, and in vivo assays.
They tested the efficacy of ebselen in a mouse model of CDI. Mice were given antibiotics (kanamycin, gentamicin, colistin, metronidazole, and vancomycin) for 3 days, then clindamycin and, 24 hours later, challenged with C difficile strain 630—a virulent and multi-drug resistant strain of epidemic type X expressing the virulence factors TcdA and TcdB. In this model, mice develop symptoms including diarrhea and pathology in the cecum and colon similar to that observed in human CDI.
Ebselen, given on days 1–5 after infection, reduced the activity of toxin present in the fecal pellet and signs of disease in the gut. Immunoblot analysis of colon tissues showed that ebselen reduced the amount of the cleaved form of toxic glucosyltransferase domain, confirming that ebselen was orally bioavailable in the colon and able to engage its target in vivo.
Oresic Bender et al analyzed sections from the cecum and proximal colon of mice given ebselen vs controls by histopathological analysis 5 days after C difficile infection. They found that mice given ebeslen had reductions in inflammatory cell infiltration, submucosal edema, and mucosal hypertrophy.
They observed a dose-dependent reduction of pathological findings in the mice receiving ebselen, with 1 mg/kg showing no improvement in histopathological score, 10 mg/kg showing partial response, and 100 mg/kg showing virtually complete response.
Their results support repurposing of ebselen, already been shown to be safe in humans, as a non-antibiotic treatment for CDI.
Medscape explained that because the drug targets the C difficile toxin, rather than the bacteria itself, it could reduce the symptoms of CDI without disrupting the host microbiome, as happens with antibiotics.
Reuters reported that ebselen is an antioxidant tested in late-stage trials by Daiichi Sankyo for treatment of stroke that never reached the market and is now off patent. The authors hope to move the drug rapidly into clinical trials for treating C difficile infection