Strengthening the Antimicrobial Arsenal of the Intestinal Epithelium to Counteract Multidrug-Resistant Enteric Pathogens
Abstract
This proposal builds upon our previous Investigator-Initiated Research Award and extends the research into a new Topic Area: Antimicrobial Resistance. The proposed studies aim to address two Areas of Encouragement that include: “development of novel and/or innovative interventions, diagnostics, and treatment for multidrug-resistant [MDR] pathogens, especially those that can be used in austere settings” and “development and evaluation of therapies to treat travelers’ diarrhea to improve the time to clinical cure and minimize resistance acquisition.” Travelers’ diarrhea has been a problem for the military as far back as the crusades in the 10th century and continues to be a major problem for modern troops. It is the second most frequent cause for hospital admission during deployment and significantly impairs combat readiness. Diarrheal disease also impacts civilian travelers, since acute infectious diarrhea is estimated to affect up to 60% of short-term international travelers. Furthermore, infectious diarrhea is a major health problem for children in developing countries where diarrhea kills over 500,000 kids annually. Additionally, 1 in 10 people with diarrheal disease go on to develop lifelong, debilitating, gastroenterological conditions. Complicating this problem is the accelerated development of MDR bacterial strains, resulting in the increased reliance on less effective or more toxic antibiotic therapies to treat infections. Clearly, there is a critical need to develop new approaches to the prevention and treatment of diarrheal disease that are safe, effective, and minimize development of bacterial multidrug resistance. In this study, we propose that increasing the strength of normal antibacterial defenses in cells that line the intestine could prevent travelers’ diarrhea or speed recovery from infection. In order to do this, we will examine how the intestine detects bacteria and defends itself from infections that cause diarrheal disease. Specifically, we will study how the bacterial sensor protein NOD2 relays signals to the nuclear CAP-D3 protein to activate an antibacterial defense program in cells from the intestine in cell culture models. Our previous work has uncovered two agents, PALA (a very stable, small molecule compound) and HA35 (a short sugar chain), which increase killing of bacteria through stimulating either NOD2 and/or CAP-D3 activity. These two agents will be given to mice before or after infection with diarrheal bacteria to determine whether increasing NOD2/CAP-D3 antibacterial defenses can prevent infection or speed resolution of infectious diarrhea. These studies will also define which components of the antibacterial defenses stimulated by the test agents are required for them to be effective, potentially identifying new therapeutic approaches for future testing. There are several benefits to this intestinal defense stimulus approach for the treatment of traveler’s diarrhea. Our data indicate that this approach will effectively kill MDR bacterial strains through activation of a multipronged response. This approach is also unlikely to contribute to the further development of bacterial drug resistance, since it does not target specific features of bacteria. This host defense-targeted approach could also be combined with existing antimicrobial treatments to increase their therapeutic effects. Furthermore, it can be used prophylactically to prevent infection by strengthening the immune defense against these bacteria, as well as a therapeutic agent after infection to speed the resolution of diarrheal infections, increasing its utility as an infection control agent. Finally, the test agents proposed to induce antimicrobial defenses, PALA and HA35, have the potential to be used in challenging settings due to their chemical stability and ability to be easily incorporated into shelf-stable powders, beverages, energy bars, or meals-ready-to-eat (MREs). Both agents have undergone testi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910488
Entities
People
- Christine McDonald
Organizations
- Cleveland Clinic
- United States Army