Targeting Shiga Toxins for Treatment-Resistant Bacterial Gut Infections
Abstract
Topic Area: Diarrheal Diseases (Second Topic: Antimicrobial Resistance) Hemorrhagic colitis (bloody diarrhea) is often caused by a Shiga toxin secreted by certain bacteria found in contaminated food or water. They cause severe symptoms and do not respond to antibiotic therapy. Over 100 million people are estimated to suffer from these infections each year, leading to 1 million deaths. In the US, there are over 700,000 infections per year. Thus, there is an urgent need for new drugs to prevent and treat these widespread infections. In this project, we propose to develop a novel class of Shiga toxin inhibitors that would block the toxin from causing diarrhea. Specifically, we will develop D-peptide inhibitors that will prevent Shiga toxins from binding to their targets in the gut wall. This will prevent diarrhea and keep the toxin out of the bloodstream. D-peptides are the mirror images of naturally occurring peptides (called L-peptides). These non-natural peptides resist degradation in the body and are poorly recognized by the immune system. As a result, D-peptides are much longer lived in the body and can be given less frequently at much lower doses at low cost. We propose to discover highly potent and specific anti-Shiga toxin D-peptides using a special screening technique (mirror-image phage display) that can simultaneously evaluate billions of peptides to identify those that block Shiga toxin most effectively. Since D-peptides are not digested in or absorbed from the gastrointestinal tract, they provide an ideal way to directly deliver a Shiga inhibitor to the gut when taken by mouth. This approach concentrates drug in the gut, reducing cost and the possibility of side effects elsewhere in the body. In this grant, we propose to discover, characterize, and optimize D-peptides that will inhibit Shiga toxin with high potency. This lead inhibitor would provide a strong foundation for the next step in drug development, including proof-of-concept efficacy studies in animal models of Shiga-mediated colitis and comprehensive animal safety studies prior to starting clinical trials in humans. In addition to providing a valuable new treatment option for Shiga-related bacterial infections, this work will serve as a prototype for a new class of anti-toxin inhibitors (since many other infectious diseases, such as cholera, are mediated by similar toxins).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810116
Entities
People
- Michael S Kay
Organizations
- United States Army
- University of Utah