Bone and joint infections affect millions of adults and children worldwide. The overall incidence in the United States is 3-6 million persons, with specific populations having different risks. for example, 1 in 30 diabetic patients have foot ulcers and up to two-thirds of these have osteomyelits. The standard of care for Bone and joint infections includes prolonged systemic administration of Antibiotics. However, the extended courses of this therapy can lead to drug-related adverse events in a significant percentage of patients. In addition, current local antibiotic delivery therapy which is through the use of antibiotic-impregnated beads and antibiotic-impregnated cement has limitations such as requiring a second procedure to remove the unabsorbable beads and burst releasing pattern of Antibiotics resulting in quick depletion of the majority of drug from the carrier beads. Bisphosphonates (BPs) are a class of therapeutic compounds used to treat Bone resorptive disorders, and accumulate in Bone with exceptionally high affinity, which makes them an excellent moiety for a novel Bone drug delivery platform. Consequently, we hypothesize that using a BP chemical moiety as a vector for the delivery of the antimicrobial agent, tedizolid (TD, an antimicrobial active against gram-positive bacteria that cause the majority of acute osteomyelitis, including methicillin-resistant Staphylococcus aureus) to Bone surfaces, could represent a pharmacologically advantageous approach to the treatment of osteomyelitis. Therefore, in this Phase I STTR project, we propose to develop a novel BP-tedizolid conjugate (BP-TD) using a releasable linker chemistry strategy, for targeted Bone delivery to effectively treat osteomyelitis. To avoid any potential effects of BP therapy on Bone remodelling or adverse events, we will utilize a pharmacologically inert BP that possesses strong Bone affinity and will serve as a safe vector for the delivery and release of the antimicrobial agent. This will allow for the greatest translational/clinical potential in future development of this technology. The use of non-pharmacologically active BP will also be helpful in delineating the source of activity in our proposed assays in order to directly study the effects of the antimicrobial agent with minimal confounders. This project will be carried out as a collaboration between BioVinc(r) LLC (Dr. Ebetino) and Joan & Sanford I. Weill medical college of Cornell University (Prof. Walsh). Dr. Ebetino and BioVinc's main focus is BP chemistry and biology as well as the design and synthesis of bisphosphonate based drug delivery systems and imaging probes. Prof. Walsh and his collaborators will bring their expertise and capabilities in microbiology and in vivo models of osteomyelitis to this project. Prof. C. E. McKenna, Ph.D. (University of Southern California), an authority on bisphosphonate chemistry and a key inventor of bisphosphonate conjugation technology, and Prof. M. N. Neely (Children's Hospital Los Angeles), an experienced clinician-scientist in the field of Pharmacokinetics and infectious diseases, will also participate as consultants. Our transdisciplinary team is uniquely poised to develop and test such a novel BP-TD compound for targeted therapeutics for osteomyelitis.
Public Health Relevance Statement: Public Health Relevance: The proposed research addresses an important and unmet medical need in the treatment of Bone infectious diseases, e.g., osteomyelitis. In a partnership involving BioVinc, LLC and the Joan & Sanford I. Weill medical college of Cornell University, a novel bisphosphonate (BP)-tedizolid conjugate will be synthesized and investigated for chronic MRSA osteomyelitis treatment in both in vitro and in vivo animal models. The outcome of this study will be the generation of a novel BP-antimicrobial conjugate specifically targeting and delivering the antimicrobial agent to infected Bone sites, with the goal of developing a highly potent and specific therapeutic treatment for preclinical research, and ultimately, clinical applications.
