Development of Innovative Therapeutics Against Pressure Ulcer-Associated Bacteria
Abstract
Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Area and Strategic Goal: We propose to develop a novel approach to treating the most problematic pressure ulcers, specifically addressing the Strategic Goal Develop and test therapeutics or dressings that enhance wound healing under the Internal Medicine Portfolio Category and Pressure Ulcers Topic Area. Millions of Americans, including many military Veterans and active Service Members, suffer from pressure ulcers annually. Pressure ulcers, or bedsores, are surface wounds caused by the weight of the body in a person unable to move normally, such as a wounded Soldier or a Veteran using a wheelchair. Most pressure ulcers heal rapidly once the pressure is relieved, but one in four pressure ulcers takes a problematic course. Despite using the best available treatment, they can take as long as a year to heal, and some never heal at all. These lesions contribute disproportionately to the billions of dollars in annual medical costs of treating pressure ulcers. Some ulcers get so deep that they can spread infection to the blood, causing blood poisoning (sepsis), a very serious condition causing thousands of deaths annually in the United States. The project aims to develop new medications for healing problematic pressure ulcers and for preventing early-stage pressure ulcers from becoming problematic. Our approach is based on the recent realization that bacteria colonize most pressure ulcers and can grow, sticking to each other and to the wound surface, to form a biofilm. The biofilm prevents the normal healing process of pressure ulcers, and the worst-affected ulcers heal poorly and become chronic wounds. Bacteria in the biofilm are protected from the immune system and survive even the most aggressive antibiotic treatment. Therefore, the biofilms are almost impossible to eradicate with currently available medications. We propose to develop a new kind of medication to address this serious problem. In our prior studies, we have discovered a universal defense system that protects bacteria from being killed by antibiotics, and we found safe chemical compounds compromising its activity. These potentiator compounds do not kill bacteria by themselves, but they make bacteria sensitive to the killing effect of many different antibiotics. Moreover, this defense system is required for forming biofilm, and when treated with our compounds, the bacteria have difficulty growing in biofilms. Thus, these compounds are promising starting points for innovative therapeutics, combining new potentiators with approved antibacterials, to effectively suppress biofilm-forming bacteria in pressure ulcers. Within the 4-year timeline of the project, we propose to: (1) design and characterize improved versions of our potentiator compounds; (2) test the results against typical bacterial biofilms formed in pressure ulcers and ulcers-associated chronic wounds by antibiotic-sensitive and -resistant strains of golden staph (Staphylococcus aureus), Pseudomonas aeruginosa, and other bacteria; (3) identify their best combinations with clinical antibacterials (antibiotics and antiseptics); and (4) evaluate the most promising combinations in animal models of pressure ulcers and sepsis. As the result, we anticipate obtaining efficacious candidate therapeutics of pressure ulcers ready for advancement toward clinical studies. Pressure ulcers and the associated complications are a serious risk for wounded U.S. Service Members and Veterans because they often follow combat injuries or other medical conditions that even temporarily preclude normal mobility or normal sensation in the skin. Over 50% casualties from Operation Iraqi Freedom had pressure ulcers. Patients confined to bed or requiring the use of a wheelchair are especially vulnerable: approximately half of Veterans with spinal cord injuries develop serious pressure ulcers during their lives. Our i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310422
Entities
People
- Alexander Serganov
Organizations
- Grossman School of Medicine
- United States Army