Bone Targeted Antibiotics

骨靶向抗生素

• 批准号: 9344983
• 负责人: Douglas H Thamm
• 金额: $ 30万
• 依托单位: MBC PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-07 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344983
• 关键词: Address; Adverse event; Aerobic; Affinity; Amputation; Anaerobic Bacteria; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Antineoplastic Agents; Automobile Driving; Bacterial Model; Binding; Blood Circulation; Blood Vessels; Bone Diseases; Bone Resorption; Cancer Patient; Chemicals; Chronic; Ciprofloxacin; Clindamycin; Cytarabine; Debridement; Deterioration; Development; Diabetes Mellitus; Dose; Drug Approval; Drug Design; Drug Kinetics; Elements; Fluoroquinolones; Generations; Goals; Growth; Histology; Histopathology; Human; Ibandronate; In Vitro; Infection; Intravenous; Investigational Drugs; Lead; Lesion; Link; Luciferases; Malignant Neoplasms; Measurement; Metastatic Neoplasm to the Bone; Methods; Modeling; Morbidity - disease rate; Nucleosides; Operative Surgical Procedures; Organism; Osteomyelitis; Patient Care; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Preparation; Procedures; Property; Recurrence; Renal clearance function; Reporting; Risk; Serious Adverse Event; Serum; Sickle Cell; Site; Staphylococcus aureus; Systemic infection; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Trauma; Trauma patient; Work; X-Ray Computed Tomography; aggressive therapy; base; bisphosphonate; bone; bone turnover; clinical application; clinically relevant; design; fluorodeoxyglucose positron emission tomography; imaging biomarker; improved; in vitro testing; in vivo; inorganic phosphate; lincosamide; methicillin resistant Staphylococcus aureus; microCT; mouse model; novel; prevent; scale up; success; systemic toxicity; targeted treatment; therapy design

Project Summary/Abstract: The overall goal of this project is to develop novel bone-targeted conjugates of clinically relevant antibiotics for the treatment of osteomyelitis. These compounds are new chemical entities built from known and approved antibiotics and bisphosphonates, which are connected via biodegradable phosphate linker. The design of these drugs exploits the high bone affinity of bisphosphonates to target the conjugate directly to the site of bone infection where both drugs are released. Proof-of-concept of this drug design as applied to cancer induced bone disease has been demonstrated in humans. We hypothesize that this design will enable the concentration of antibiotic in bone to currently unachievable levels while also reducing systemic exposure. Such conjugates may have a wider therapeutic range than currently available therapies, and as an added benefit, the drugs also strengthen the bones and may reverse the deterioration of bone, associated with infection. The proposed studies will enable the preparation of a four novel conjugates that will be characterized in vitro and assessed for efficacy in a mouse model of osteomyelitis. The specific aims of this project are: (1) Develop synthetic methods and make sufficient amounts of four conjugates composed of one of two bisphosphonates classes (etidronate or ibandronate) and two antibiotics (ciprofloxacin or clindamycin); (2) Demonstrate efficacy in a luciferase based mouse model of osteomyelitis, reduction or elimination of bone localized staphylococcus aureus and (in a parallel model) psuedomonous aeruginosa and assess the microarchitecture of bone with histology, imaging and markers of bone turnover. The successful completion of this Phase I project will guide the further development of this promising concept, identify a lead compound to be carried into FDA required studies for investigational new drug approval, and lead to eventual clinical application. It is anticipated that this technology will ultimately result in therapeutic agents that will significantly improve osteomyelitis patient care resulting in decreased morbidity and reduced amputations and reduced antibiotic related toxicities as well as reduce the risk of infection for routine surgery and bone-exposed trauma patients.

项目摘要/摘要： 该项目的总体目标是开发临床相关抗生素的新型骨靶向结合物 骨髓炎的治疗。这些化合物是由已知和批准的化合物构建而成的新化学实体 抗生素和双膦酸盐，通过可生物降解的磷酸盐连接体连接。这些的设计 药物利用双膦酸盐的高骨亲和力将缀合物直接靶向骨部位 两种药物都释放的感染。该药物设计应用于癌症诱导的概念验证 骨骼疾病已在人类身上得到证实。我们假设这种设计将能够集中 骨中抗生素的含量达到目前无法达到的水平，同时还减少了全身暴露。此类缀合物 可能比目前可用的疗法具有更广泛的治疗范围，并且作为额外的好处，这些药物还 强化骨骼，并可能逆转与感染相关的骨骼退化。拟议的 研究将能够制备四种新型缀合物，并对其进行体外表征和评估 用于骨髓炎小鼠模型的疗效。本项目的具体目标是：（1）开发合成 方法并制备足够量的由两种双膦酸盐类之一组成的四种缀合物 （依替膦酸或伊班膦酸）和两种抗生素（环丙沙星或克林霉素）； (2) 展示功效 基于荧光素酶的骨髓炎小鼠模型，减少或消除骨局部金黄色葡萄球菌 和（在平行模型中）假单胞菌铜绿菌并通过组织学评估骨的微结构， 骨转换的成像和标记。一期工程的顺利完成，将为下一步的发展指明方向。 开发这一有前途的概念，确定一种先导化合物，以进行 FDA 所需的研究 研究性新药批准，并导致最终的临床应用。预计这 技术最终将产生显着改善骨髓炎患者的治疗药物 护理可降低发病率、减少截肢并减少抗生素相关毒性 并降低常规手术和骨外伤患者的感染风险。