The pathogenic bacterium Clostridioides difficile (C. diff) causes highly recurrent gastrointestinal infections that plague the healthcare system. These infections are difficult to treat, and the bacteria are difficult to eradicate from contaminated environments, because C. diff is highly resilient to extracellular stresses caused by the mammalian immune system and by antibiotics. The Purcell lab studies the molecules that transmit information from the environment to C. difficile sensory systems, and from sensors to stress response pathways.
The development of more effective treatments for C. diff infection has been slow because so little is known about this bacterium—its scientific name is actually due to the difficulty researchers had in isolating and growing it! Research has been slow because C. diff is an obligate anaerobe, an organism that is poisoned by oxygen. While is can form dormant spores that survive in oxygen and spread the infection to new patients, researchers have difficulty studying the active form of the bacteria that causes disease. As a result, we know very little about how it moves around and selects locations to attach to. The Purcell group has built a device to allow microscopic investigation of live C. diff. We have demonstrated that C. diff stops moving and attaches to surfaces in the presence of sialic acid, a component of intestinal mucus. This is the first indication that C. diff regulates its motility in response to nutrient availability, and suggests that testing to diagnose C. diff infection should be performed on the mucus that lines the intestines and not just the intestinal contents. Now that we have shown that C. diff stops swimming and settles down in the presence of 'good' substances like nutrients, we are eager to see if it tries to swim away and avoid 'bad' substances like antibiotics.
We have also focused on small ribonucleotide signals—guanosine tetraphosphate and pentaphosphate (together called (p)ppGpp)—that some bacteria synthesize under stress. We were the first group to show that C. diff makes these signals, and we have developed molecular reporters to identify which antibiotics stimulate (p)ppGpp production. We have discovered that a low affinity inhibitors of (p)ppGpp synthetase enzymes reduce C. diff antibiotic resistance, and are working to characterize the C. diff enzymes to enable the development of high-affinity inhibitors that could be administered with antibiotics to make them more effective against C. diff.