title: Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms.
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.
authors.forename: Parish P
authors.identifier: 0000-0003-4190-0497
authors.initials: PP
authors.lastname: Sedghizadeh
authors.affiliation: BioVinc, LLC , Pasadena, California 91107, United States.
authors.forename: Shuting
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Microbiology and Parasitology, Wrocław Medical University , Wroclaw 50-367, Poland.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Junka
authors.affiliation: BioVinc, LLC , Pasadena, California 91107, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Richard
authors.affiliation: BioVinc, LLC , Pasadena, California 91107, United States.
authors.forename: Keivan
authors.identifier: 0000-0003-3166-7257
authors.initials: K
authors.lastname: Sadrerafi
authors.forename: Susan
authors.initials: S
authors.lastname: Mahabady
authors.forename: Neema
authors.initials: N
authors.lastname: Bakhshalian
authors.forename: Natalia
authors.initials: N
authors.lastname: Tjokro
authors.affiliation: Department of Pharmaceutical Microbiology and Parasitology, Wrocław Medical University , Wroclaw 50-367, Poland.
authors.forename: Marzenna
authors.initials: M
authors.lastname: Bartoszewicz
authors.affiliation: Department of Pharmaceutical Microbiology and Parasitology, Wrocław Medical University , Wroclaw 50-367, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Oleksy
authors.affiliation: Centre for Advanced Manufacturing Technologies, Wrocław University of Technology , Wrocław 50-370, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Szymczyk
authors.affiliation: BioVinc, LLC , Pasadena, California 91107, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lundy
authors.affiliation: BioVinc, LLC , Pasadena, California 91107, United States.|Department of Pharmacology and Medicine, Pennsylvania State University College of Medicine , Hershey, Pennsylvania 17033, United States.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Neighbors
authors.affiliation: The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford , Oxford OX3 7LD, United Kingdom.|The Mellanby Centre for Bone Research, Department of Oncology and Metabolism, University of Sheffield , Sheffield S10 2RX, United Kingdom.
authors.forename: R Graham G
authors.initials: RG
authors.lastname: Russell
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.affiliation: BioVinc, LLC , Pasadena, California 91107, United States.
authors.forename: Frank H
authors.initials: FH
authors.lastname: Ebetino
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D018441:Biofilms / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000382:microbiology; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D005260:Female; D010019:Osteomyelitis / Q000188:drug therapy* / Q000382:microbiology; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D004164:Diphosphonates; D002939:Ciprofloxacin