Targeted Drug Neutralizes C difficile Toxins in Animal Model

Lara C. Pullen, PhD

September 23, 2015

A nonantibiotic drug (ebselen) reduced the pathology of Clostridium difficile infection (CDI) in an animal study. The findings raise the possibility that ebselen, which is already in clinical trials for the treatment of other conditions, can be developed as a therapy for the treatment of CDI.

Also, because the drug targets the C difficile toxin, and not the bacteria itself, there is the possibility that it could reduce the symptoms of CDI without disrupting the host microbiome, as happens with antibiotics.

Kristina Oresic Bender, PhD, from the Stanford University School of Medicine in California, and colleagues published the results from their mouse model of CDI online September 23 in Science Translational Research. They treated the mice 2 hours before infection with C difficile to optimally assess the effect of ebselen on toxin-mediated pathology. Their mouse model did not allow them to assess rates of recurrent infection.

"I think this is exciting, and it is really a tour de force of translational drug development," enthused Elizabeth Louise Hohmann, MD, from Massachusetts General Hospital in Boston, in an interview with Medscape Medical News. Dr Hohmann is not affiliated with the research, but she reviewed the study for the interview.

C difficile Toxins

CDI encompasses a wide range of diarrheal illnesses that are caused by the large clostridial toxins (TcdA and TcdB) produced by C difficile. Although previous therapeutic approaches have been directed at these toxins, such efforts have not been successful before this month.

Ebselen targets these major virulence determinants of CDI pathology and appears to represent a viable alternative treatment strategy to the commonly used antibiotics.

"The drug has already been tested in humans, and there isn't a huge safety signal," elaborated Dr Hohmann. Ebselen also has the advantage of being an oral agent.

The publication of the study on ebselen joins reports from the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) of another therapeutic advance in the treatment of CDI. Investigators reported at the meeting that a monoclonal antibody to one of the toxins was able to effectively treat recurrent CDI. The monoclonal antibody, however, has the disadvantage of being an intravenous drug.

Mechanism of Action

Ebselen appears to protect cells against TcdB by blocking cysteine protease domain–mediated processing of the glucosyltransferase domain.

"Although our combined results strongly suggest that ebselen functions by blocking [glucosyltransferase domain] release, recent findings demonstrating that toxin-induced cell death is dependent on [reactive oxygen species] raise the possibility that ebselen could also confer some level of protection via its antioxidant effect.... Although this study could not uncouple any potential antioxidant functions of ebselen from its effects on the [cysteine protease domain] domain, any added antioxidant effects of ebselen would serve to enhance the efficacy of the drug by using multiple mechanisms to generate therapeutic benefit," the authors write.

They conclude by suggesting that ebselen may not only improve the symptoms of initial onset of CDI but also help restore the natural microbiota of the patient.

Dr Hohmann believes such a hypothesis remains to be tested. Nonetheless, "this is exciting, because it could be most useful in the patients who are really sick and are already getting standard of care, but are not getting better," added Dr Hohmann.

Several of the authors are listed on a provisional patent for ebselen. Dr Hohmann is a consultant and clinical investigator for Seref Therapeutics.

Sci Transl Med. Published online September 23, 2015.


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