Host Targeted Therapy for Drug Resistant Salmonella and Francisella infection

耐药沙门氏菌和弗朗西斯氏菌感染的宿主靶向治疗

基本信息

批准号：
9145977
负责人：
Kristy M Ainslie
金额：
$ 140.68万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-22 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145977
关键词：
ADME Study AKT Signaling Pathway Acetates Acids Anti-Bacterial Agents Antibiotic Resistance Antibiotics Autophagocytosis Bacteria Bacterial Drug Resistance Bacterial Infections Biocompatible Materials Biological Biological Assay Biomedical Engineering Camptothecin Categories Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemical Structure Chemistry Clinical assessments Computer software Data Development Dextrans Drug Design Drug resistance Encapsulated Excipients Excretory function Formulation Francisella Francisella tularensis Genes Goals Grant Growth Health Care Costs Host Defense Mechanism Human In Vitro Infection Infection prevention Institutes Institution Isoenzymes Lead Life Cycle Stages Malignant Neoplasms Maximum Tolerated Dose Metabolism Methods Minimum Inhibitory Concentration measurement Modeling Multi-Drug Resistance Mus National Institute of Allergy and Infectious Disease North Carolina PDH kinase Paclitaxel Pathway Analysis Pathway interactions Phagocytes Pharmaceutical Chemistry Pharmaceutical Preparations Phase I Clinical Trials Polymers Process Production Proto-Oncogene Proteins c-akt Public Health Research Research Personnel Resistance Safety Salmonella Salmonella enterica Salmonella typhi Salmonella typhimurium Structure System Taiwan Testing Therapeutic Time Tissue-Specific Gene Expression Toxic effect Toxicology Universities Virulence Work absorption abstracting analog base design drug candidate drug development drug mechanism drug resistant bacteria experience fighting improved in vivo inhibitor/antagonist killings macrophage meetings nanoparticulate novel particle pathogen pre-clinical pressure prevent research study resistant strain scaffold targeted treatment therapeutic target therapy development transcriptome sequencing

项目摘要

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.

抽象的抗菌药物抗药性的形成是一种公共卫生危机，导致增加医疗保健费用甚至死亡。当抗生素直接杀死病原体或由于选择性压力而防止其增长。这种现象已经产生了各种抗多药细菌物种是全球公共卫生问题。大多数抗菌疗法靶向病原体，试图清除感染。但是，更多最近，已经开发了针对宿主特定途径的抗菌疗法的概念。这些途径可以潜在地防止感染，病毒，复制和增殖。针对这些的治疗途径可能可能治疗传统的抗生素抗性菌株。另外，针对主机而不是病原体可以防止耐药性发展，因为该治疗可以激活途径这种抵制并激活了宿主的防御机制。 futhermore，因为许多病原体服用相似途径的优势，有可能开发针对广泛光谱的疗法病原体。我们是使用宿主靶向疗法（HTT）治疗病原体的首批组之一疾病预防控制中心认为这是严重的威胁水平。该HTT无法直接在细胞内工作病原体，但靶向宿主细胞促进导致病原体清除的途径。此外，该HTT具有针对病原体的广谱活性，包括niaID类别A类病原体。我们有体外和体内数据都显示活性和生存率增加。为了增加活动，我们有将这种化合物封装在一种对酸敏感的新型生物材料中。这种酸灵敏度允许封装货物的细胞内释放。我们的初步数据表明，HTT的封装很大与非封装形式相比，提高化合物的效率。在此提案中，我们建议在HTT上进行药物化学，以开发与活动增加。我们将用于体外和体内的新型聚合物颗粒中制定该化合物测试。我们将执行各种生物学测定，以确定优化化合物的活性。为了做这是我们的建议是北卡罗来纳大学，台湾大学和研究三角研究所（RTI）。这种伙伴关系对于获得优化的HTT化合物将是无价的这具有针对各种病原体的活动，因为它使该领域的学术研究人员不合适，并且 RTI在药物开发方面的经验。