Antibiotics are critical to the success of surgical procedures, especially those using implantable biomaterials. However, antibiotic resistance is increasing rapidly, with some bacterial strains resistant to every commercial antibiotic (1). Orthopaedic infections are some of the most challenging to treat, with severe consequences for patients. There remains an unmet clinical need for the development and application of novel antibiotics. Peptidomimetics are a new class of antibiotic in preclinical development that address the drawbacks of current antibiotic therapy. They are inspired by natural antimicrobial peptides, that disrupt bacterial cell membrane integrity, resulting in rapid cell lysis (2). Due to their unique mechanism of action, these compounds have activity against antibiotic-resistant bacterial isolates, biofilm activity and a lower propensity of resistance development (3). In this study we assessed the biocompatibility of a two novel peptidomimetics, Melimine and RK758, when loaded into bone allograft. A critical-size defect was made in a rabbit distal femur defect model and filled with peptidomimetic loaded bone allograft. Bone healing was assessed across 3, 6 and 12 week timepoints. Histology of the defect site was used to assess the host tissue response and the formation of new bone in the presence of test implant materials. Bloodwork analysis and histology of the major organs were assessed for any signs of systemic toxicity. No adverse reactions were noted for any of the peptidomimetic treatment groups. Comparative micro-computed tomography analysis revealed a similar increase in bone surface area and volume between peptidomimetic groups and controls. By 12-weeks, the defects were completely closed with mature bone and bone marrow. In conclusion, peptidomimetics offer a novel solution for the prevention and treatment of antibiotic-resistant infections. This study supports the advance of these compounds in the antibiotic research and development pipeline.