Disarm, not destroy

The bacterium Clostridium difficile wreaks havoc in hospitals — and in patients’ guts. It grabs a foothold in those with weakened immune systems, harms their intestines and is hard to get rid of. It kills 15,000 people in the United States each year.

C. difficile infection has traditionally been treated with antibiotics, which unfortunately also wipe out microbes that can resist such pathogens. Infection recurs in a quarter of those treated — and only a quarter of those recover with further antibiotics.

In a series of experiments, researchers at the School of Medicine have demonstrated that the drug ebselen can disable C. difficile’s toxins, rather than destroying it entirely. “Unlike antibiotics — which are both the front-line treatment for C. difficile infection and, paradoxically, possibly its chief cause — the drug didn’t kill the bacteria,” says senior author Matthew Bogyo, PhD, professor of pathology and of microbiology and immunology.

The team knew C. difficile’s two main toxins were secreted proteins with similar sections of protease activity — proteins that slice up other proteins. They tested 120,000 molecules against the primary toxin. Hundreds shut down the protease activity, but they zeroed in on ebselen because it has already been used safely in clinical trials for other conditions. Subsequent experiments demonstrated that ebselen reduced the clinical symptoms of C. difficile infection and blocked persistent gut damage in mice.