The goal of this project is to develop novel methods for the prevention and treatment of orthopaedic infections following traumatic injuries including those incurred on the battlefield. Using Staphylococcus aureus as a proof-of-principle pathogen based on its prominence as a cause of such infections and the severity of the infections its causes, we have undertaken studies to identify the most efficacious antibiotics and investigate the ability to conjugate these antibiotics to a novel bone targeting agent derived from a tetracycline moiety that binds hydroxyapatite. We have also demonstrated that the staphylococcal accessory regulator (sarA) plays a key role in the pathogenesis of orthopaedic infections owing in part to its impact on biofilm formation and intrinsic antibiotic resistance. Based on this, we have undertaken a search for small molecule inhibitors that could be used alone or in combination with conventional antibiotics and our bone targeting agent. Ultimately, these combinations will be evaluated based on their therapeutic efficacy in established animal models of traumatic bone infection.