Broad Spectrum Host-Oriented Therapy for Wound Infection
Abstract
Objectives/Rationale: During combat, Warfighters are subject to trauma-induced wounds, often associated with burn injury, which upon bacterial infection may rapidly progress to a lethal outcome. In recent years, there has been a dramatic increase in the ability of bacteria to resist antibiotics previously effective in treating these infections. The World Health Organization and the Centers for Disease Control and Prevention have identified antibiotic resistance as a major global health problem, and the White House considers this situation a national security concern. With the dwindling antibiotic development pipeline, clinicians are left to use less effective, more toxic antibiotics. We developed a novel therapeutic approach using small proteins, or peptides, which prevent the excessive, harmful inflammation responsible for much of the pathology and lethality of severe, life-threatening wound infections, including those caused by bacteria resistant to antibiotics. In this project, we intend to compare this promising peptide treatment with additional peptides that may possess greater protective activity. We will compare the ability of different peptides to improve survival in mice lethally infected with methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PA), and Klebsiella pneumoniae (KP), bacteria commonly associated with wound infections, including those resistant to antibiotics, or given a lethal dose of a superantigen toxin from MRSA that causes toxic shock. Peptides that show the greatest promise in improving survival will then be tested in mice that undergo a nonlethal burn and infected with KP, PA, or MRSA. The ability of the peptides to protect the mice from lethal burn wound infection and to prevent disseminated infection will be determined. Peptides most effective in improving survival against these bacteria will then be tested in burn wounds infected with multidrug-resistant bacteria isolated from combat-related wound infections. At the conclusion of our study, we intend to identify one or more peptides for further development. Our experience with a prototype peptide, p2TA, provides a path for the manufacture, regulatory assessment, and clinical trial of the selected peptide(s). This project aligns directly with the Fiscal Year 2017 Applied Research Award focus on combat- or trauma-related wound infections caused by multi-drug resistant organisms (MDROs), particularly MRSA, KP, and PA, including carbapenem-resistant organisms. The proposed research will greatly impact the focus area. There has not been a new class of antimicrobials effective against Gram-negative bacteria, such as KP and PA, for over 40 years. In the absence of effective treatment, patients infected with these MDROs may require surgery to remove dead tissue (including amputation) or die from disseminated infection and sepsis. The peptides we intend to develop are not sensitive to the mechanisms used by bacteria to evade antibiotics and do not induce resistance in bacteria. Our prototype peptide, p2TA, has already shown promising results in reducing the pathology in patients with trauma-induced infections in a Phase 2 trial, and was very well tolerated. Since the peptides have activity against a broad spectrum of bacteria known to cause wound infection and are safe and well-tolerated, peptides shown to be effective in this study can be administered in the field by medics even before the bacteria in wounds are identified. They may also enable the Warfighter to return to duty more rapidly. Since the peptides are designed to reduce the excessive inflammatory response caused by bacteria, viruses (e.g., pandemic influenza), and non-infectious inflammation (e.g., arthritis), there is potential for widespread clinical application to multiple inflammatory syndromes. The prototype peptide, p2TA, has also been shown to reduce morbidity and mortality associated with radiation enteritis. Compared to other biologics
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710416
Entities
People
- Alan Cross
Organizations
- United States Army
- University of Maryland, Baltimore