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

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.