Novel Cell-Penetrating Peptide-Nucleic Acid to Induce "Suicide" via Newly Identified Toxin-Antitoxin System in MDR Pseudomonas aeruginosa Biofilm
Abstract
This project addresses Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area Antibiotic Resistance. In particular, we are addressing the area of encouragement “Development of novel and/or innovative interventions to prevent the spread of or treatment of infections from multidrug-resistant organisms, focused on hardware-associated infections and biofilms.” Central Critical Problem: Multidrug-resistant (MDR) organisms cause a large number of infections in the Warfighter, especially following blast and burn wounds incurred in battle, or subsequent orthopedic surgeries. MDR organisms are a common and very difficult-to-treat cause of hardware-associated infections, which are mediated by tightly associated biofilms, rendering them even more difficult to eradicate. Up to 24% of Veterans have diabetes, much higher than the 9% in the general US population, putting them at risk for diabetic foot wounds and chronic non-healing ulcers. These ulcers and wounds are often infected with MDR bacteria, commonly MDR Pseudomonas and MDR Acinetobacter, which form biofilms in the wound bed, inhibiting healing and prolonging the infection. Both of these pathogens are dangerous infections for the Warfighter and also for Veterans and military family members. MDR organisms cause an estimated 155,000 deaths in America per year, affecting Veterans and the families of Warfighters, and very few new antibiotics are being developed especially against gram-negative bacteria. Thus, novel approaches to treating MDR gram-negative infections are needed. Our research is aimed at lowering the number of MDR-mediated infections through targeting MDR organisms. Innovation: We propose to produce a novel precision antimicrobial strategy that is genetically targeted at these MDR biofilm-producing bacteria. We will target a recently discovered bacterial toxin-antitoxin system as a novel antimicrobial approach, by inducing “suicide” of the bacteria. By interfering with the antitoxin gene expression using peptide-nucleic acid constructs, the toxin will then be free to act on the bacteria from the inside, killing the bacteria. These “suicide-inducing” constructs will be selected for strong activity against MDR Pseudomonas aeruginosa in a pre-formed biofilm, such as would be found in a hardware-associated or diabetes wound infection. Ultimate Applicability and Impact of Research: This research is highly applicable to Warfighter blast or burn infections, infections resulting from orthopedic implants, and infections of chronic non-healing ulcers, such as found in diabetic patients. The peptide-nucleic acids that will be designed could be used in combination with standard-of-care antibiotics to help eliminate the bacteria and the biofilms in these important infections of MDR bacteria.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010049
Entities
People
- Monique van Hoek
Organizations
- George Mason University
- United States Army