Bone targeted antimicrobials for biofilm-mediated osteolytic infection treatment

 描述（由申请方提供）：感染性骨病是全球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抗生素治疗。细菌生物膜病原体与大多数骨感染相关，并且代表治疗的主要靶点。与慢性骨感染相关的生物膜病原体结合并定植在骨表面上。双膦酸盐（BPs）是广泛使用的抗吸收药物，其也结合到骨表面，并且因此已被用于治疗溶解性骨病变，如骨质疏松症、多发性骨髓瘤和转移性骨疾病。因此，我们假设使用BP化学部分作为载体，用于将抗微生物剂环丙沙星（CF）递送至骨表面（生物膜病原体驻留的地方），可以代表治疗颌骨感染性骨病的非常有利的方法。因此，在这个I期STTR项目中，我们建议使用可释放的连接体化学策略开发新型BP-环丙沙星缀合物（BP-CF），用于靶向骨递送以有效治疗颌骨感染。为了避免BP治疗对骨重建或不良事件的任何潜在影响，我们将使用具有强骨亲和力的生物惰性BP，并将作为抗菌剂递送和释放的安全载体。这将使该技术在未来的发展中具有最大的转化/临床潜力。使用非生物活性BP也将有助于在我们提出的测定中描绘活性来源，以便直接研究生物活性。 抗微生物剂的作用，混杂因素最少。本项目将由BioVinc（r）LLC（Ebetino博士）和USC（Sedghizadeh教授）合作开展。Ebetino博士和BioVinc的主要重点是BP化学和生物学以及基于双膦酸盐的药物递送系统和成像探针的设计和合成。Sedghizadeh教授及其合作者将把他们在生物膜微生物学和溶骨性感染的新型体外和体内模型方面的专业知识和能力带到这个项目中。C教授E. McKenna博士（南加州大学），双膦酸盐化学的权威和“魔术连接剂”技术的关键发明者，R. K. Boeckman（罗切斯特大学），合成有机化学和合成双膦酸盐类似物的专家，和M。N. Neely（洛杉矶儿童医院）是药代动力学和传染病领域经验丰富的临床科学家，也将作为顾问参加。我们的跨学科团队是唯一准备开发和测试新型BP-CF化合物的传染性骨疾病的靶向治疗。

 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.