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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.

摘要