Host Targeted Therapy for Drug Resistant Salmonella and Francisella infection

摘要 抗菌素耐药性的形成是一种公共健康危机，并导致越来越多的 医疗费用，甚至死亡。当抗生素直接杀死病原体或 由于选择性的压力，阻止了它的生长。这种现象已经产生了各种多药耐药 细菌种类是全球公共卫生关注的问题。 大多数抗菌治疗药物都针对病原体，试图清除感染。然而，更多 最近，针对宿主特定途径的抗菌疗法的概念已经发展起来。这些 途径可以潜在地防止感染、毒力、复制和扩散。针对这些的疗法 途径可能治疗传统的抗生素耐药菌株。此外，目标是主机，而不是 这种病原体可以阻止耐药性的发展，因为治疗可以激活通路 对抗抵抗并激活宿主的防御机制。此外，因为许多病原体携带 类似途径的优势，有可能开发针对广泛的 病原体。 我们是首批使用宿主靶向治疗(HTT)治疗病原体的小组之一。 疾控中心认为这是严重的威胁级别。这种HTT不能直接作用于细胞内 而不是针对宿主细胞，而是促进病原体清除的途径。另外， 该HTT对包括NIAID A类病原体在内的病原体具有广谱活性。我们有 体外和体内数据都显示出活性和存活率的增加。为了增加活动，我们有 将这种化合物包裹在一种对酸敏感的新型生物材料中。这种对酸的敏感性允许 细胞内释放被包裹的货物。我们的初步数据显示，HTT的封装大大 与非囊化形式相比，增强了该化合物的功效。 在这项提案中，我们建议对我们的HTT进行药物化学处理，以开发一种具有 活跃度增加。我们将在我们的新型聚合物颗粒中配制这种化合物，用于体外和体内。 测试。我们将进行各种生物测试，以确定优化的化合物的活性。为了做某事 这个，我们的建议是北卡罗来纳大学，国立台湾大学和 三角研究所(RTI)。这种伙伴关系在获得优化的HTT化合物方面将是无价的。 它对广泛的病原体具有活性，因为它参与了该领域的学术研究人员和 RTI在药物开发方面的经验。

Abstract The formation of antibacterial drug resistance is a public health crisis and has led to increaseing healthcare costs and even death. Drug resistance can occur when an antibiotic directly kills a pathogen or prevents its growth because of selective pressure. This phenomena has generated various multi-drug resistant bacterial species that are a global public health concern. Most antibacterial therapeutics target the pathogen in an attempt to clear infection. However, more recently the concept of antibacterial therapeutics that target host specific pathways has been developed. These pathways can potentially prevent infection, virulence, replication, and proliferation. Therapies that target these pathways could potentially treat traditional antibiotic resistant strains. Additionally, targeting the host instead of the pathogen could prevent the development of drug resistance because the therapy could activate pathways that fight resistance and activate the host’s defense mechanisms. Futhermore, because many pathogens take advantage of similar pathways, there is a potential for developing therapies that target a broad-spectrum of pathogens. We were one of the first groups to use a host-targeted therapeutic (HTT) for the treatment of a pathogen that is considered a Threat Level of Serious by the CDC. This HTT does not work directly on intracellular pathogens but instead targets host cell promoting pathways that result in clearance of the pathogen. Additionally, this HTT has broad-spectrum activity against pathogens including a NIAID Category A class pathogen. We have both in vitro and in vivo data showing activity and increase in survival. In order to increase activity we have encapsulated this compound in a novel biomaterial that is acid sensitive. This acid sensitivity allows for the intracellular release of encapsulated cargo. Our preliminary data shows that encapsulation of the HTT drastically enhances the efficacy of the compound compared to non-encapsulated form. In this proposal, we propose on performing medicinial chemistry on our HTT to develop a compound with increased activity. We will formulate this compound in our novel polymeric particles for both in vitro and in vivo testing. We will perform various biological assays to determine activity of optimized compounds. In order to do this, our proposal is a partnership between the University of North Carolina, National Taiwan University, and the Research Triangle Institute (RTI). This partnership will be invaluable in obtaining an optimized HTT compound that has activity against a broad spectrum of pathogens as it incoporates academic researchers in the field and RTI’s experience with drug development.