Bone targeted antimicrobials for biofilm-mediated osteolytic infection treatment

 描述(申请人提供)：感染性骨病是世界范围内发病率和死亡率的主要原因。成功的治疗通常需要手术干预和长期的抗生素治疗。细菌生物被膜病原体与大多数骨感染有关，是治疗的主要靶点。与慢性骨感染相关的生物膜病原体结合并定植于骨表面。双膦酸盐(BPS)是一种广泛使用的抗吸收药物，也与骨表面结合，因此已被用于治疗骨质疏松、多发性骨髓瘤和转移性骨疾病等溶骨性疾病。因此，我们推测，使用BP化学部分作为载体将抗菌剂环丙沙星(CF)输送到骨表面(生物被膜病原体所在的地方)，可能是治疗颌骨感染性骨病的一种药物优势方法。因此，在这个第一阶段的STTR项目中，我们建议开发一种新型的BP-环丙沙星结合物(BP-CF)，使用可释放的连接物化学策略，用于靶向性骨传递，以有效治疗颌骨感染。为了避免BP治疗对骨重建的任何潜在影响或不良事件，我们将利用一种药理上的惰性BP，它具有很强的骨亲和力，将作为安全的载体输送和释放抗菌剂。这将使这项技术在未来的发展中具有最大的转化/临床潜力。使用非药理活性BP也将有助于在我们建议的分析中描绘活性来源，以便直接研究 具有最小混杂的抗菌剂的效果。该项目将由BioVinc(R)LLC(Ebetino博士)和南加州大学(Sedghizadeh教授)合作实施。埃贝蒂诺博士和BioVinc的主要业务是BP化学和生物学，以及基于双膦酸盐的药物输送系统和成像探测器的设计和合成。Sedghizadeh教授和他的合作者将把他们在生物膜微生物学和新型体外和体内溶骨感染模型方面的专业知识和能力带到这个项目中。双膦酸盐化学和“魔术链接器”技术关键发明人C.E.McKenna教授(南加州大学)博士、双膦酸类化合物合成有机化学和合成专家R.K.Boeckman教授和洛杉矶儿童医院在药物动力学和传染病领域经验丰富的临床医生兼科学家M.N.Neely教授也将作为顾问参加。我们的跨学科团队独一无二地准备开发和测试用于感染性骨病靶向治疗的新型BP-CF化合物。

 DESCRIPTION (provided by applicant): Infectious bone disease is a major cause of morbidity and mortality worldwide. Successful treatment often requires surgical intervention with longer-term antibiotic therapy. Bacterial biofilm pathogens are associated with most osseous infections and represent a major target of therapy. The biofilm pathogens associated with chronic bone infections bind to and colonize on bone surfaces. Bisphosphonates (BPs) are widely used antiresorptive medications that also bind to bone surfaces, and have therefore been utilized to treat lytic bone pathoses like osteoporosis, multiple myeloma, and metastatic bone disease. Consequently, we hypothesize that using a BP chemical moiety as a vector for the delivery of the antimicrobial agent, ciprofloxacin (CF) to bone surfaces (where biofilm pathogens reside), could represent a pharmacologically advantageous approach to the treatment of infectious bone disease in the jaw. Therefore, in this Phase I STTR project, we propose to develop a novel BP-ciprofloxacin conjugate (BP-CF) using a releasable linker chemistry strategy, for targeted bone delivery to effectively treat jawbone infections. To avoid any potential effects of BP therapy on bone remodelling or adverse events, we will utilize a pharmacologically inert BP that possesses strong bone affinity and will serve as a safe vector for the delivery and release of the antimicrobial agent. This will allow for the greatest translational/clinical potential in future development of this technology. The use of a non-pharmacologically active BP will also be helpful in delineating the source of activity in our proposed assays in order to directly study the effects of the antimicrobial agent with minimal confounders. This project will be carried out as a collaborative between BioVinc(r) LLC (Dr. Ebetino) and USC (Prof. Sedghizadeh). Dr. Ebetino and BioVinc's main focus is BP chemistry and biology as well as design and synthesis of bisphosphonate based drug delivery systems and imaging probes. Prof. Sedghizadeh and his collaborators will bring their expertise and capabilities in biofilm microbiology and in novel in vitro and in vivo models of osteolytic infections to this project. Prof. C. E. McKenna, Ph.D. (University of Southern California), an authority on bisphosphonate chemistry and "magic linker" technology key inventor, Prof. R. K. Boeckman (University of Rochester), an expert in synthetic organic chemistry and synthesis of bisphosphonate analogs, and Prof. M. N. Neely (Children's Hospital Los Angeles), an experienced clinician-scientist in the field of pharmacokinetics and infectious diseases, will also participate as consultants. Our transdisciplinary team is uniquely poised to develop and test the novel BP-CF compound for targeted therapeutics for infectious bone disease.