Infectious bone disease is a major cause of morbidity and mortality worldwide. Successful treatment often requires surgical intervention with longer-term antibiotic therapy. Bacterial biofilm pathogens are associated with most osseous infections and represent a major target of therapy. The biofilm pathogens associated with chronic bone infections bind to and colonize on bone surfaces. Bisphosphonates (BPs) are widely used antiresorptive medications that also bind to bone surfaces, and have therefore been utilized to treat lytic bone pathoses like osteoporosis, multiple myeloma, and metastatic bone disease. Consequently, we hypothesize that using a BP chemical moiety as a vector for the delivery of the antimicrobial agent, ciprofloxacin (CF) to bone surfaces (where biofilm pathogens reside), could represent a pharmacologically advantageous approach to the treatment of infectious bone disease in the jaw. Therefore, in this Phase I STTR project, we propose to develop a novel BP-ciprofloxacin conjugate (BP-CF) using a releasable linker chemistry strategy, for targeted bone delivery to effectively treat jawbone infections. 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 a 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 collaborative between BioVinc(r) LLC (Dr. Ebetino) and USC (Prof. Sedghizadeh). Dr. Ebetino and BioVinc's main focus is BP chemistry and biology as well as design and synthesis of bisphosphonate based drug delivery systems and imaging probes. Prof. Sedghizadeh and his collaborators will bring their expertise and capabilities in biofilm microbiology and in novel in vitro and in vivo models of osteolytic infections to this project. Prof. C. E. McKenna, Ph.D. (University of Southern California), an authority on bisphosphonate chemistry and magic linker technology key inventor, Prof. R. K. Boeckman (University of Rochester), an expert in synthetic organic chemistry and synthesis of bisphosphonate analogs, 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 the novel BP-CF compound for targeted therapeutics for infectious bone disease.
The proposed research addresses an important and unmet medical need in the treatment of bone infectious diseases, e.g., jaw infections. In a partnership involving BioVinc, LLC and the Ostrow School of Dentistry at the University of Southern California, the novel bisphosphonate (BP)-ciprofloxacin prodrug conjugate will be synthesized and investigated for biofilm-mediated osteolytic infection treatment in an in vitro and in vivo animal model. The outcome of this study will be the generation of the novel BP-antimicrobial prodrug 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.
|Sedghizadeh, Parish P; Sun, Shuting; Junka, Adam F et al. (2017) Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms. J Med Chem 60:2326-2343|