Synthesis and Characterization of Bone Binding Antibiotic-1 (BBA-1), a Novel Antimicrobial for Orthopedic Applications

Abstract

Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the design and synthesis of a novel bone-binding antibiotic (BBA-1) and its subsequent structural and functional characterization. The synthesis of BBA-1 was the result of a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90) and the bisphosphonate alendronate (ALN) via a heterobifunctional linker. This was analytically confirmed by HPLC, FT-IR, MS and NMR spectroscopy. BBA-1 showed rapid binding and high affinity to bone mineral in an in vitro hydroxyapatite binding assay. Kirby–Baur assays confirmed that BBA-1 shows a potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus comparable to CSA-90. Differentiation of cultured osteoblasts in media supplemented with BBA-1 led to increased alkaline phosphatase expression, which is consistent with the pro-osteogenic activity of CSA-90. Bisphosphonates, such as ALN, are inhibitors of protein prenylation, however, the amine conjugation of ALN to CSA-90 disrupted this activity in an in vitro protein prenylation assay. Overall, these findings support the antimicrobial, bone-binding, and pro-osteogenic activities of BBA-1. The compound and related agents have the potential to ensure lasting activity against osteomyelitis after systemic delivery.

Strategies to Mitigate and Treat Orthopaedic Device-Associated Infections

“…Multi-drug combinations or the combination of drugs with either antimicrobial materials or quorum-sensing inhibitors have also been investigated to enhance the antibacterial spectrum, create synergy and circumvent the risk of bacterial resistance. More recently, attempts to develop novel antimicrobials for orthopaedic applications investigated bone-binding antibiotic (BBA-1), which was produced via a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90), and the bisphosphonate, alendronate [ 100 ]. BBA-1 demonstrated rapid binding to bone mineral and showed potent antibacterial activity against S. aureus and MRSA in vivo.…”