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Molecular target of a novel broad-spectrum antiviral and antibacterial compound

新型广谱抗病毒和抗菌化合物的分子靶标

基本信息

批准号：
9334099
负责人：
DANIEL D ROCKEY
金额：
$ 17.85万
依托单位：
OREGON STATE UNIVERSITY
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：
2016-08-20 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334099
关键词：
Address Affect Anti-Bacterial Agents Anti-Infective Agents Antimicrobial Resistance Antiviral Agents Area Bacteria Base Sequence Biological Assay Biomedical Research Caring Cell Line Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Chlamydia Communicable Diseases Coronaviridae Coronavirus Coxiella burnetii Cycloheximide Cytostatics Data Dengue Development Disease Ebola virus Encephalomyocarditis virus Fluorescence Freedom Future Gene Targeting Genes Goals Grant Growth Growth and Development function HIV-1 Hantavirus Haploid Cells Haploidy Health Professional Human Human Cell Line In Vitro Individual Infection Infection Control Infectious Agent Influenza Knock-out La Crosse virus Laboratories Lead Letters Libraries Metabolic Pathway Molecular Target Morbidity - disease rate Multi-Drug Resistance Mutate Mutation Neisseria gonorrhoeae Oregon Pathway interactions Pattern Population Positioning Attribute Primates Process Proteins Research Resistance Secretory Immunoglobulin A Sequence Analysis Small Interfering RNA Structure System TNFSF5 gene Technology Therapeutic Thinking Thiourea Toxic effect United States National Institutes of Health Universities Vaccinia Virus Work Zoonoses antimicrobial bacterial resistance base design experimental study fighting high throughput screening knock-down macromolecule methicillin resistant Staphylococcus aureus mortality mutant novel novel therapeutics pathogen public health relevance screening small molecule tool virtual whole genome

项目摘要

DESCRIPTION (provided by applicant): The importance of new anti-infective strategies cannot be overstated. Emergence of new conditions caused by previously unknown infectious agents, in combination with the rapid increase in known and novel antimicrobial-resistant pathogens, has led to crises in therapeutic options that require new ways of thinking. One approach to this problem is the development of novel anti-infective compounds that can address aspects of the problem. Our laboratories have identified and characterized a novel thiourea-based small molecule, termed ST-669 that has low-micromolar activity against a wide variety of viruses as well as the intracellular bacteria Chlamydia and Coxiella burnetii. Viruses sensitive to the action of ST-669 include vaccinia (EC-50 = 0.25 micromolar), ebola, influenza, HIV-1, dengue, encephalomyocarditis virus, and Lacrosse virus. (EC-50 = 0.27 micromolar). The overall goal of this project is to identify the mechanism of action of ST-669. The compound is active only in cells of primate origin and activity is sensitive to treatment of cells with cycloheximide. The collected data surrounding ST- 669 activity lead us to hypothesize that the compound works by upregulating a host protein or metabolic pathway. Therefore, our two aims use complementary approaches to knock out (Aim 1) or knock down (Aim 2) all possible genes in cells of human origin and looking for individual mutations that abrogate the inhibitory effects of the compound. In Aim 1, a haploid human cell line will be randomly mutated using a retroviral gene trap approach and the collected mutated populations screened for elimination of ST-669 activity. In Aim 2, we will use a global siRNA library in a high throughput screening strategy to knock down individual protein abundance, and examine treated cells for lack of ST-669 activity. Growth of Chlamydia caviae will be used in this screening approach, in a high throughput assay routinely used in the laboratory. Secondary screens for each assay will be conducted and the resulting data examined for consistencies and inconsistencies. These results will position our laboratories to develop hypothesis-driven experiments to elucidate the specific mechanism of action of ST-669, and to design approaches to target this pathway in future small molecule screens. These experiments may also identify novel tools used by cells to control infections by very different groups of intracellular pathogens.