Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms

Parish P. Sedghizadeh, Shuting Sun, Adam F. Junka, Eric Richard, Keivan Sadrerafi, Susan Mahabady, Neema Bakhshalian, Natalia Tjokro, Marzenna Bartoszewicz, Monika Oleksy, Patrycja Szymczyk, Mark W. Lundy, Jeffrey D. Neighbors, R. Graham G. Russell, Charles E. McKenna, Frank H. Ebetino

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a “target and release” chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 μmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 μmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure.

Original languageEnglish (US)
Pages (from-to)2326-2343
Number of pages18
JournalJournal of Medicinal Chemistry
Volume60
Issue number6
DOIs
StatePublished - Mar 23 2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Sedghizadeh, P. P., Sun, S., Junka, A. F., Richard, E., Sadrerafi, K., Mahabady, S., Bakhshalian, N., Tjokro, N., Bartoszewicz, M., Oleksy, M., Szymczyk, P., Lundy, M. W., Neighbors, J. D., Russell, R. G. G., McKenna, C. E., & Ebetino, F. H. (2017). Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms. Journal of Medicinal Chemistry, 60(6), 2326-2343. https://doi.org/10.1021/acs.jmedchem.6b01615