Small Molecule Tames Gut Pathogen C. Difficile Rather Than Killing It

A small, selenium-containing molecule can protect mice from the pathogenic bacterium Clostridium difficile, according to a new study. The compound doesn’t kill the microbes, which cause about 500,000 infections every year in the U.S. Instead the molecule shuts down the bacterial toxin that wreaks havoc in the guts of its hosts.

“The work represents an exciting validation of the concept that inhibiting toxin function by a small molecule can lead to benefits in preventing C. difficile pathogenesis,” says Roman A. Melnyk, a biochemist at the Hospital for Sick Children, in Toronto, who was not involved in the work.

Ironically, people typically acquire C. difficile infections while taking broad-spectrum antibiotics in the hospital. The drugs knock down the patient’s normal gut flora, allowing C. difficile to take over. The sometimes-fatal infection leads to diarrhea and inflammation of the colon.

Doctors usually treat the infection with antibiotics such as vancomycin, but the bacteria are resilient: In about 20% of patients, the infection comes back at least once.

To find a nonantibiotic strategy for treating C. difficile, some researchers have started to look for ways to neutralize the microbe’s toxin, a multidomain protein that damages endothelial cells in the intestines. Last week, Merck Co. announced data from a Phase III clinical trial of an antibody that targets the C. difficile toxin.

Matthew Bogyo of Stanford University School of Medicine and colleagues wanted to find a small molecule that could inhibit the toxin’s protease domain. Once the toxin gets into the cytoplasm of endothelial cells, the protease cleaves off the glucosyltransferase domain (GTD), allowing this cell-damaging portion of the protein to run free in the cell.

Through a high-throughput screen for inhibitors of the protease domain, the researchers found ebselen, a compound currently in clinical trials as a treatment for chemotherapy-induced hearing loss.

In mice infected with C. difficile, ebselen completely blocked release of GTD in the animals’ colons, resulting in a reduction of inflammation and damage caused by the pathogen (Sci. Transl. Med. 2015, DOI: 10.1126/scitranslmed.aac9103).

Through mass spectrometry studies, Bogyo’s team determined that ebselen works via its selenium, which reacts with a critical cysteine in the active site of the protease domain.

Melnyk wonders whether ebselen’s structure may need tweaking to make sure its selenium specifically hits the toxin’s cysteine and not others in host cells. Still, he thinks the compound’s simple structure is a promising starting point for small molecules that block the C. difficile toxin.