Enhancing the Prevention and Treatment of Orthopaedic Infections Associated with Traumatic Injury
Abstract
Infections of bone present a unique and complex clinical problem. Although these infections can arise via any one of several mechanisms, among the most common, and the most problematic, are infections arising as a result of traumatic injury. This is particularly true of open fractures, which are among the most common times of injuries suffered by Soldiers in combat. Indeed, not only is the rate of infection very high following such injuries, but the difficulties in resolving the infection are magnified by several factors including a compromised blood supply, the need for orthopaedic hardware to restore structural stability, and formation of a biofilm on the bone and/or this associated hardware. Thus, developing methods for the prevention and treatment of these infections is an urgent clinical imperative of extreme importance to military personnel who serve in combat situations. Accomplishing this is the specific focus of the research we propose. To this end, we explore evaluate new antibiotics that are active against methicillin-resistant Staphylococcus aureus (MRSA), which is the leading cause of such infections, in the specific context of their efficacy in a biofilm. We will then determine whether the most promising of these antibiotics can be conjugated to our bone targeting agent without compromising this efficacy. We will also take advantage of our studies demonstrating the important role of the staphylococcal accessory regulator (sarA) in S. aureus biofilm formation and bone infection to identify and optimize small molecule inhibitors of sarA-mediated regulatory functions and to assess whether these inhibitors can also be conjugated to our bone targeting agent without compromising the inhibitory activity. We will then combine these two efforts by assessing the extent to which these inhibitor bone-targeted conjugates can be used, both alone and in combination with our optimized antibiotic conjugates, to prevent and treat orthopaedic infections arising as a result of traumatic injuries including those incurred on the battlefield.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510716
Entities
People
- Mark S Smeltzer
Organizations
- United States Army
- University of Arkansas for Medical Sciences