Hospital acquired Clostridium difficile bug defense system identified

By Dr. Ananya Mandal, MDAug 23 2011

American researchers have discovered the process by which the cells in the gut fight off toxins produced by a hospital bug - Clostridium difficile. Writing in Nature Medicine, they showed how a chemical - GSNO - deactivated a toxin from Clostridium difficile which causes inflammation and diarrhea. They hope to use their findings to develop a treatment for C. difficile.

C. difficile is one of many bacteria which can live in the human gut without causing health problems. Understanding how this mechanism deactivates toxins provides a basis for developing new therapies that can target toxins directly said Dr Jonathan Stamler of Case Western Reserve University.

A course of antibiotics, which wipes out other bacteria in the gut, can allow C. difficile to multiply in the bowels. They produce large numbers of toxins which enter the cells lining the bowel. This damages the cells resulting in inflammation, cramps, fever, diarrhea and blood-stained stools. It is particularly a problem in hospitals as the bacteria can spread, and many patients could be taking antibiotics or have a weakened immune system. In hospitals in England there were 10,414 C. difficile infections during the financial year 2010-11, down from 33,442 in 2007-08.

The whole toxin is unable to penetrate cells so it needs to cleave off a smaller bits. Scientists have identified the chemical GSNO - S-nitrosoglutathione - which is produced by the bowels in response to inflammation. It can bind to the toxin, preventing cleavage, so the toxin cannot enter cells.

Dr Jonathan Stamler said, “Understanding how this mechanism deactivates toxins provides a basis for developing new therapies that can target toxins directly and thereby keep bacterial infections, like C. diff, from spreading.” In experiments on mice, the study showed giving the chemical orally increased survival. Researchers now want to begin clinical trials.

Lead author Prof Tor Savidge, from the University of Texas, believes the technique could be used on other infections. “Along with its potential to provide a much-needed new approach to treating Clostridium difficile infection, the discovery could be applied to developing new treatments for other forms of diarrhea, as well as non-diarrheal diseases caused by bacteria,” he said.

Prof Nigel Minton, from the Clostridia Research Group at the University of Nottingham, said, “This is an exciting discovery. Anything that can add to our scant arsenal of available treatments for combating this devastating disease is an important step forward. Having said that, one imagines that an actual therapeutic based on this discovery is some way off, either from being developed, and more importantly, from entering the clinic.”

“We are treating a disease caused by antibiotics with yet another antibiotic, which creates the conditions for re-infection from the same bacteria,” study co-author Charalabos Pothoulakis, MD, stated in the release. “Identification of new treatment modalities for treat this infection would be a major advance.” “We already know through gene-sequencing analysis that hundreds of microbial proteins can be regulated by s-nitrosylation,” Pothoulakis stated. “If we are successful with this approach, we may be able to treat other bacterial diseases in a similar way.”