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

J Med Chem. 2017 Mar 23;60(6):2326-2343. doi: 10.1021/acs.jmedchem.6b01615. Epub 2017 Feb 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Bacteria / drug effects
  • Bacterial Infections / drug therapy
  • Bacterial Infections / microbiology
  • Biofilms / drug effects
  • Bone and Bones / drug effects
  • Bone and Bones / microbiology
  • Ciprofloxacin / analogs & derivatives*
  • Ciprofloxacin / pharmacology
  • Ciprofloxacin / therapeutic use*
  • Diphosphonates / chemistry*
  • Diphosphonates / pharmacology
  • Diphosphonates / therapeutic use*
  • Drug Design
  • Female
  • Osteomyelitis / drug therapy*
  • Osteomyelitis / microbiology
  • Rats, Sprague-Dawley
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / physiology

Substances

  • Anti-Bacterial Agents
  • Diphosphonates
  • Ciprofloxacin