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 language | English (US) |
|---|---|
| Pages (from-to) | 2326-2343 |
| Number of pages | 18 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 60 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 23 2017 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery
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Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms. / Sedghizadeh, Parish P.; Sun, Shuting; Junka, Adam F.; Richard, Eric; Sadrerafi, Keivan; Mahabady, Susan; Bakhshalian, Neema; Tjokro, Natalia; Bartoszewicz, Marzenna; Oleksy, Monika; Szymczyk, Patrycja; Lundy, Mark W.; Neighbors, Jeffrey; Russell, R. Graham G.; McKenna, Charles E.; Ebetino, Frank H.
In: Journal of Medicinal Chemistry, Vol. 60, No. 6, 23.03.2017, p. 2326-2343.Research output: Contribution to journal › Article
TY - JOUR
T1 - Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms
AU - Sedghizadeh, Parish P.
AU - Sun, Shuting
AU - Junka, Adam F.
AU - Richard, Eric
AU - Sadrerafi, Keivan
AU - Mahabady, Susan
AU - Bakhshalian, Neema
AU - Tjokro, Natalia
AU - Bartoszewicz, Marzenna
AU - Oleksy, Monika
AU - Szymczyk, Patrycja
AU - Lundy, Mark W.
AU - Neighbors, Jeffrey
AU - Russell, R. Graham G.
AU - McKenna, Charles E.
AU - Ebetino, Frank H.
PY - 2017/3/23
Y1 - 2017/3/23
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.6b01615
DO - 10.1021/acs.jmedchem.6b01615
M3 - Article
VL - 60
SP - 2326
EP - 2343
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 6
ER -