Using implantable biomaterial and bio-orthogonal chemistry to guide delivery of antibiotics

摘要 抗药性细菌的崛起是对美国人口和世界其他地区健康的主要威胁 世界。每年有200万美国人遭受抗生素耐药性感染。根据疾控中心的说法，至少 2013年，这些感染直接导致23,000人丧生，更多的人死于与 并发症。每年抗生素耐药性给医疗保健系统造成的损失超过200亿美元 住院时间缩短了6.4-12.7天，社会又损失了350亿美元的生产力。减少了20% 抗生素耐药感染每年将节省32亿至52亿美元的医疗成本。但对抗生素有抗药性 由于不分青红皂白和不必要地使用广谱抗生素，感染率正在上升 医疗保健和农业。如果没有有效的抗生素，标准药物治疗后的轻微感染可能会 会带来毁灭性的后果。基于植入物的手术是一个特别令人担忧的问题。手术现场 感染(SSI)每年在美国发生在超过78万名患者中，并导致8205人死亡。种植体 相关感染占这些SSI的20%，即超过35,000起事件和估计2,000起 死亡。在美国，仅髋关节和膝关节置换手术每年就导致2万例SSI，而这些 患者在医院多呆两周，医疗费用增加两倍，显著减少 生活质量。随着美国人口继续老龄化，髋关节和膝盖置换将发生在更大的 频率，耐药感染的数量也会增加。不幸的是，大多数全身性抗生素 治疗指数有限，目前使用的剂量可能会促使细菌发展 抵抗。全身抗生素还会损害身体其他部位的正常细菌菌群，从而进一步 鼓励抵抗，并允许机会性感染不受控制地蓬勃发展。此外，最系统性的 药物和外用抗生素在穿透手术后组织方面效果不佳。理想情况下，应该提供 仅在感染区域需要确切剂量的抗生素，这将使药物能够对抗 同时避免全身副作用，降低细菌耐药性的可能性。在那里的时候 是作为药物仓库的植入性材料，药物不能被调节或修改 植入后。这些方法通常需要物理植入和移除，并导致 最初的药物突发，然后几天或几周，药物以亚治疗水平释放， 有可能导致产生抗药性细菌。沙斯基正在开发一项技术，该技术基于一种捕获物和 两种生物正交化学物质之间的“释放”反应，导致局部药物释放。这种方法 将可注射生物材料的空间控制与全身灭活前药的时间控制相结合 送货。根据该项目，沙奇将利用这项技术开发万古霉素和万古霉素的可释放前体药物。 达托霉素是治疗耐甲氧西林金黄色葡萄球菌感染的“最后药物”。这样做的具体目的是 项目是建立受试化合物的体外最低抑菌浓度(MIC)；并研究 化合物在局部耐甲氧西林金黄色葡萄球菌感染小鼠模型中。

Abstract The rise of antibiotic-resistant bacteria is a major threat to the health of the U.S. population and the rest of the world. 2 million Americans suffer from antibiotic-resistant infections yearly. According to the CDC at least 23,000 lives were lost in 2013 as a direct result of these infections and many more die due to related complications. Every year antibiotic resistance costs the healthcare system more than $20 billion, extends hospital stays by 6.4-12.7 days, and costs society another $35 billion in lost productivity. A 20% reduction in antibiotic-resistant infections would save $3.2-$5.2 billion each year in healthcare costs. But antibiotic-resistant infections are on the rise due to the indiscriminate and unnecessary use of broad-spectrum antibiotics in healthcare and agriculture. Without effective antibiotics, trivial infections after standard medical therapies could have devastating consequences. Surgeries based on implants are a particular source of concern. Surgical-site infections (SSIs) occur in more than 780,000 patients and cause 8,205 deaths in the U.S. each year. Implant associated infections account for 20% of those SSIs, i.e., more than 35,000 incidents and an estimated 2,000 deaths. Hip and knee replacement surgeries alone lead to 20,000 SSIs each year in the U.S., and these patients suffer an additional two weeks in the hospital, a tripled cost of healthcare, and a significantly reduced quality of life. As the U.S. population continues to age, hip and knee replacements will occur with greater frequency, and so will the number of antibiotic-resistant infections. Unfortunately, most systemic antibiotics have a limited therapeutic index, and the doses that are currently used may drive bacteria to develop resistance. Systemic antibiotics also harm normal bacterial flora in other parts of the body, which further encourages resistance and allows opportunistic infections to flourish unchecked. Furthermore, most systemic drugs as well as topical antibiotics are poor at penetrating post-operative tissue. Ideally one would provide the exact dose of antibiotic needed exclusively at the area of infection, which would enable the drug to fight the bacteria while avoiding systemic side effects and reducing the likelihood of bacterial resistance. While there are implantable materials that serve as depots of medication, the medications cannot be modulated or modified after implantation. These methods usually require physical implantation and removal, as well as result in an initial burst of medication followed by days or weeks where the drug is released at sub-therapeutic levels, potentially leading to antibiotic-resistant bacteria. Shasqi is developing a technology based on a `catch and release' reaction between two bio-orthogonal chemicals that results in a localized drug release. This approach combines the spatial control of injectable biomaterials with the temporal control of systemic inactive prodrug delivery. Under this project, Shasqi will use this technology to develop releasable prodrugs of vancomycin and daptomycin, which are commonly used as “drugs of last resort” for MRSA infections. The specific aims of this project are to establish minimum inhibitory concentration (MIC) of the test compounds in vitro; and study the compounds in a mouse model of local MRSA infection.