Targeting the Innate Immune Response to Combat Antibiotic-Resistant Bacterial Infections
Abstract
This proposal focuses on the Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area Healthcare-Acquired Infection Reduction through the development of a new antimicrobial for the treatment of emerging multidrug-resistant (MDR), healthcare-associated infections. Infection is a major cause of morbidity and mortality associated with combat-related injuries, with approximately one-third of casualties from recent military conflicts in Iraq and Afghanistan developing an infectious complication. Of critical concern are the increasing antimicrobial resistance of these strains and the decreasing availability of effective treatments for these MDR strains. Additionally, despite rigorous infection control measures, there is a high rate of hospital-acquired infection with MDR strains within treatment facilities and during international air evacuation of injured personnel. Therefore, there is a critical need to develop new approaches to combat MDR bacterial infections. We are developing a new antimicrobial compound to enhance protective immune responses in the skin as a new way to combat MDR bacterial infections. One key component of the first line of anti-bacterial defense in the skin is a sensor protein called nucleotide-binding, oligomerization domain 2 (NOD2). We have discovered that NOD2 activity is controlled by an enzyme called CAD (carbamoyl phosphate synthetase/aspartate transcarbamylase/dihydroorotase). CAD can be turned off by an existing anti-cancer drug and this dramatically increases NOD2 activity. We found that increasing NOD2 activity in this way resulted in the enhanced killing of multiple pathogenic bacterial strains, many of which are members of the ESKAPE pathogen family (i.e., Enterococcus faecium, S. aureus, Klebsiella pneumonia, A. baumannii, P. aeruginosa, and Enterobacter species) that are agents responsible for the majority of nosocomial infections and have high rates of antibiotic resistance. We have also seen in experiments with human skin that a topical treatment with this CAD inhibitor drug was as effective as a triple antibiotic ointment in reducing methicillin-resistant S. aureus (MRSA) infection. Our findings suggest that enhancement of NOD2 antimicrobial function is achievable and displays therapeutic potential against a broad range of bacteria. We predict that activation of this multifaceted antimicrobial defense program will target a broad range of bacterial strains, avoid the further development of MDR organisms, and could be combined with existing antimicrobial treatments to potentiate a therapeutic response. However, more testing needs to be done to prove this. Therefore, we will test this NOD2-stimulating drug in preclinical models of MDR bacteria-infected wounds to determine the potential therapeutic effectiveness of this immune system boosting approach. We will also perform detailed experiments in human cells to more clearly understand how this drug specifically increases NOD2 activity to see if there are other potential drug targets that would be even more effective to use. The potential clinical impact of these studies is the identification of a novel therapeutic agent for the treatment of MDR bacterial infections acquired within healthcare treatment facilities and during transport of injured military personnel. Our results would have broad implications for infection control in both military and civilian populations. The current studies will only be carried out in animal models, but the results of these studies have the potential to be rapidly applied to a preclinical trial. Our long-term goal is to produce a sustained impact on the approach to healthcare acquired infection control by stimulating the development and application of therapeutics that target normal protective responses rather than targeting a specific bacterial strain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610439
Entities
People
- Christine McDonald
Organizations
- Cleveland Clinic
- United States Army