Development of Gut-Restricted Bile Acid Analogs Inhibitory to C. difficile Infection
Abstract
The human intestine contains highly organized and complex microbial communities, termed “microbiota,” which function as an organ that participates in digestion and interacts with the body to instruct the immune system and maintain overall human health. However, the mutually beneficial relationship between these microbes and their human host has been under severe assault from the widespread use of broad-spectrum antibiotics. This has led to emergence of multidrug-resistant pathogens, which constitute a growing urgent threat to our entire healthcare system. Among some 18 such pathogens identified by the Centers for Disease Control and Prevention, Clostridium difficile tops the list. C. difficile causes a diarrheal illness that strikes nearly 500,000 people per year in the US alone and results in about 30,000 deaths. The main trigger for this infection is antibiotic use, which kills many gut bacteria and allows Clostridium difficile to gain a foot-hold in the intestinal tract. Paradoxically, antibiotics are currently also the standard treatment for this antibiotic-associated disease. Not surprisingly, antibiotic treatments also commonly fail and actually increase susceptibility to recurrence of the disease. This is due in large part to the fact that C. difficile produces spores, which are resting stages of bacteria that are highly resistant to antibiotics and very difficult to eradicate from the environment. When antibiotic treatment is eventually stopped, the C. difficile spores germinate producing viable toxin-producing cells. After the first round of antibiotic treatment for C. difficile infection, the risk of its recurrence within a couple weeks is 20%-30%. With every new round of antibiotic treatment, the chance of another recurrence goes up by another 20%. Thus, approximately 100,000 patients develop a syndrome of indefinite recurrences of symptomatic infection that is untreatable by existing antibiotics. Over the last 10 years, fecal microbiota transplantation (FMT) has emerged as a highly effective option for many patients with recurrent C. difficile infections, and we have been leaders in the development of standardized microbial preparations for disease treatment. Our proposal builds on our investigations of how FMT works in the treatment of CDI. We have discovered that bile acids play a major role in controlling C. difficile germination and vegetative growth. Bile acids are synthesized in the liver and transported into the digestive tract to aid in digestion. Some bile acids are modified by colon bacteria into a form that inhibits germination of C. difficile spores. Antibiotics kill these colon bacteria, preventing modification of bile acids and allowing C. difficile spores to germinate. FMT restores these essential colon bacteria, allowing them to produce bile acids that inhibit C. difficile. Although this treatment option is an important advance in this field, it has limited benefit for many patients, including people that require antibiotics for other indications and many patients with underlying inflammatory bowel disease. Therefore, instead of FMT, why not just feed people bile acids that control C. difficile? Unfortunately, none of the natural inhibitory bile acids are suitable for use as therapeutics due to their rapid transport out of the intestine before they have a chance to prevent spore germination. In our preliminary studies, we have identified a number of bile acid derivatives that inhibit the germination of spores of clinically relevant strains of C. difficile with greater potency than the natural bile acids. We have also identified chemical modifications to bile acids that should make the compounds stay in the gut long enough to do their job. Our central idea is that gut-restricted bile acid-based therapeutic compounds can be developed that will be potent inhibitors of C. difficile and will be useful clinically. The overall objectives of our proposal is to develop bile acid
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710635
Entities
People
- Peter I Dosa
Organizations
- United States Army
- University of Minnesota