Division of Periodontology, Diagnostic Sciences and Dental Hygiene, Infection and Immunity Laboratory, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90007, USA.
BioVinc LLC, Pasadena, CA 91107, USA.
Int J Mol Sci. 2023 Jan 19;24(3):1985. doi: 10.3390/ijms24031985.
Osteomyelitis is a limb- and life-threatening orthopedic infection predominantly caused by biofilms. Bone infections are extremely challenging to treat clinically. Therefore, we have been designing, synthesizing, and testing novel antibiotic conjugates to target bone infections. This class of conjugates comprises bone-binding bisphosphonates as biochemical vectors for the delivery of antibiotic agents to bone minerals (hydroxyapatite). In the present study, we utilized a real-time impedance-based assay to study the growth of biofilms over time and to test the antimicrobial efficacy of our novel conjugates on the inhibition of biofilm growth in the presence and absence of hydroxyapatite. We tested early and newer generation quinolone antibiotics (ciprofloxacin, moxifloxacin, sitafloxacin, and nemonoxacin) and several bisphosphonate-conjugated versions of these antibiotics (bisphosphonate-carbamate-sitafloxacin (BCS), bisphosphonate-carbamate-nemonoxacin (BCN), etidronate-carbamate-ciprofloxacin (ECC), and etidronate-carbamate-moxifloxacin (ECX)) and found that they were able to inhibit biofilms in a dose-dependent manner. Among the conjugates, the greatest antimicrobial efficacy was observed for BCN with an MIC of 1.48 µg/mL. The conjugates demonstrated varying antimicrobial activity depending on the specific antibiotic used for conjugation, the type of bisphosphonate moiety, the chemical conjugation scheme, and the presence or absence of hydroxyapatite. The conjugates designed and tested in this study retained the bone-binding properties of the parent bisphosphonate moiety as confirmed using high-performance liquid chromatography. They also retained the antimicrobial activity of the parent antibiotic in the presence or absence of hydroxyapatite, albeit at lower levels due to the nature of their chemical modification. These findings will aid in the optimization and testing of this novel class of drugs for future applications to pharmacotherapy in osteomyelitis.
骨髓炎是一种主要由生物膜引起的危及肢体和生命的骨科感染。骨骼感染在临床上极难治疗。因此，我们一直在设计、合成和测试新型抗生素缀合物以靶向骨骼感染。这类缀合物包括与骨结合的双膦酸盐，作为将抗生素递送至骨矿物质（羟磷灰石）的生化载体。在本研究中，我们利用实时阻抗测定法来研究生物膜随时间的生长，并测试我们的新型缀合物在存在和不存在羟磷灰石的情况下抑制生物膜生长的抗菌功效。我们测试了早期和新一代喹诺酮类抗生素（环丙沙星、莫西沙星、司他沙星和奈诺沙星）以及这些抗生素的几种双膦酸盐缀合版本（双膦酸盐-氨基甲酸酯-司他沙星（BCS）、双膦酸盐-氨基甲酸酯-奈诺沙星（BCN）、依替膦酸盐-氨基甲酸酯-环丙沙星（ECC）和依替膦酸盐-氨基甲酸酯-莫西沙星（ECX）），发现它们能够以剂量依赖的方式抑制生物膜。在缀合物中，BCN 的抗菌效果最好，MIC 为 1.48µg/mL。缀合物的抗菌活性因用于缀合的特定抗生素、双膦酸盐部分的类型、化学缀合方案以及存在或不存在羟磷灰石而异。在这项研究中设计和测试的缀合物保留了母体双膦酸盐部分的骨结合特性，这一点通过高效液相色谱得到了证实。它们还保留了在存在或不存在羟磷灰石的情况下母体抗生素的抗菌活性，尽管由于其化学修饰的性质，活性较低。这些发现将有助于优化和测试这一新类药物，以将其用于骨髓炎的药物治疗。
