Bone targeted delivery of an antimicrobial drug for osteomyelitis therapy

DESCRIPTION provided by applicant Bone and joint infections affect millions of adults and children worldwide The overall incidence in the United States is million persons with specific populations having different risks For example in 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 andamp Sanford I Weill Medical College of Cornell University Prof Walsh Dr Ebetino and BioVincandapos 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 Childrenandapos 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 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 andamp 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