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- Title
Synthesis and Characterization of Bone Binding Antibiotic-1 (BBA-1), a Novel Antimicrobial for Orthopedic Applications.
- Authors
Kamble, Sumedh; Valtchev, Peter; Dao, Aiken; Pelras, Théophile; Rogers, Michael J; Savage, Paul B.; Dehghani, Fariba; Schindeler, Aaron; Barrajon, Enrique
- 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.
- Subjects
BINDING site assay; METHICILLIN-resistant staphylococcus aureus; ALKALINE phosphatase; NUCLEAR magnetic resonance spectroscopy; ISOPRENYLATION
- Publication
Molecules, 2021, Vol 26, Issue 6, p1541
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules26061541