Description:
Executive Summary
University of Virginia researchers have created novel derivative compounds of FDA-approved drug Nitazoxanide (NTZ) that show reduced toxicity, improved bioavailability and greater efficacy against a range of organisms that cause diarrheal diseases.
Background
Diarrheal diseases are especially common in children, immuno-compromised individuals, people living in developing nations, international travelers, patients undergoing long-term hospitalization and nursing home residents. Infectious diarrheal diseases are the second-highest global cause of morbidity and mortality. Complications from infection include malnutrition, dysentery, liver abscess and death; repeated or prolonged episodes can stunt the growth of children and impair cognition. Despite advances and improvements in health care, diarrheal diseases continue to exert a staggering disease burden worldwide, underscoring the need for novel therapies.
Nitazoxanide (NTZ) is an FDA-approved drug for the treatment of G. lamblia and C. parvum infections. It also shows broad spectrum activity in vitro against anaerobic bacteria, such as C. difficile, H. pylori and C. jejuni. NTZ, however, is poorly soluble in ethanol and insoluble in water. In addition, following oral administration of NTZ, 99 percent of the active metabolite is protein bound.
About the Invention
Paul S. Hoffman, Ph.D., and colleagues at the University of Virginia have determined the molecular target of NTZ and are using a structure–activity relationship (SAR) approach to design novel NTZ derivative compounds. To date, more than 200 compounds have been synthesized, yielding 50 lead compounds that are more effective than NTZ in vitro against a range of organisms causing diarrheal diseases. The compounds were first tested in vitro for the ability to inhibit growth of C. difficile, C. jejuni and E. coli. Additionally, compounds were found to prevent EAEC biofilm formation, a critical step in persistent colonization and resistance to antibiotics. Preliminary testing in mice shows very low toxicity, and PK/PD and dosing studies are under way. Lead compounds are also currently being tested in mouse models of C. difficile and E. histolytica infections and show protective effects via oral administration.
The compounds show inhibitory activity in vitro against other disease-causing organisms, including H. pylori, S. aureus and S. epidermidis. A description of NTZ-derivative effects on these organisms can be found online. The organisms are also predicted to be effective against all anaerobic bacteria and parasites based on the conservation of molecular target pyruvate ferredoxin oxidoreductase (PFOR).
Advantages
These novel compounds offer the following advantages over alternative therapeutics:
- Improved solubility and bioavailability over NTZ
- Low incidence of toxicity and side effects
- Broad spectrum activity
- Proven efficacy in mouse models
