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Discovery of Hsp100-selective inhibitors for targeting multiple microbial pathogens

发现针对多种微生物病原体的 Hsp100 选择性抑制剂

基本信息

批准号：
10440373
负责人：
Anuradha Roy
金额：
$ 32.87万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440373
关键词：
ATP phosphohydrolase Affinity Antibiotic Resistance Antibiotics Binding Biochemical Biological Assay Biological Testing Biology Cells Chemicals Communicable Diseases Data Development Disease Drug resistance Dysentery ESKAPE pathogens Enteral Escherichia coli Family Funding Opportunities Future Goals Gram-Negative Bacteria Growth In Vitro Infection Investigation Kansas Knowledge Laboratories Lead Libraries Malaria Molecular Molecular Chaperones Orthologous Gene Outcome Parasites Pathogenicity Penetration Pharmaceutical Chemistry Plasmodium falciparum Proteins Proteome Public Health Quality Control Research Rod Role Shigella Shigella flexneri Shigella sonnei Staphylococcus aureus Structure Testing Therapeutic Agents United States National Institutes of Health Universities Validation Virulence antimicrobial antimicrobial drug assay development base biological adaptation to stress clinical application clinically relevant clinically significant combat cytotoxicity drug discovery healthcare community high throughput screening inhibitor innovation microbial microorganism mortality novel novel strategies pathogen pathogenic microbe resistant strain screening small molecule small molecule inhibitor small molecule libraries

项目摘要

PROJECT SUMMARY/ABSTRACT Pathogenic microorganisms are the cause of diverse infections and diseases worldwide. The emergence of drug resistant strains increases the infection and mortality rates and demands new approaches and efforts in the antimicrobial drug discovery. The long-term goal of our research is to understand the role of molecular chaperones in pathogen growth, survival, and virulence and to apply that knowledge in developing molecular approaches to combat infectious diseases. The objective of this application is to discover small-molecule inhibitors of Hsp100 chaperones using high-throughput library screening. The Hsp100 chaperones reactivate aggregated cellular proteins. A loss of Hsp100 is detrimental for infectivity and survival of a number of bacterial and protozoan pathogens. Importantly, no apparent Hsp100 orthologs are found in metazoan proteomes. As the primary target for inhibitor development and testing, we will use the Hsp100 chaperone, ClpB, from Shigella/Escherichia coli. The following Specific Aims will be pursued: 1. We will perform a sequence of two screens of a small-molecule library that will interrogate two orthogonal functionalities of ClpB: ATP-dependent substrate binding and substrate-induced activation of the ATPase activity. 2. We will validate and prioritize compound hit chemotypes that inhibit ClpB using medicinal chemistry approaches. 3. We will validate the inhibitory potency of selected hit compounds and test their selectivity towards ClpB in vitro by performing a number of orthogonal biochemical assays. 4. We will perform preliminary testing of the antimicrobial activity of the hit compounds in Gram-negative bacteria Escherichia coli, Shigella flexneri, and Shigella sonnei, and Gram-positive Staphylococcus aureus. The expected outcome of the proposed studies will be the discovery of validated small-molecule Hsp100-inhibitor candidates for future medicinal chemistry optimization and biological testing. This approach is innovative because no chaperone-based antimicrobials have been implemented yet.

项目概要/摘要病原微生物是全世界多种感染和疾病的原因。的出现耐药菌株增加了感染率和死亡率，需要新的方法和努力抗菌药物的发现。我们研究的长期目标是了解分子的作用病原体生长、生存和毒力中的伴侣，并将这些知识应用于开发分子对抗传染病的方法。该应用的目的是发现小分子使用高通量文库筛选 Hsp100 分子伴侣抑制剂。 Hsp100 伴侣重新激活聚集的细胞蛋白质。 Hsp100 的缺失不利于许多细菌的感染性和生存和原生动物病原体。重要的是，在后生动物蛋白质组中没有发现明显的 Hsp100 直向同源物。作为作为抑制剂开发和测试的主要目标，我们将使用 Hsp100 分子伴侣 ClpB，来自志贺氏菌/大肠杆菌。我们将追求以下具体目标： 1. 我们将执行两个序列小分子库的筛选将询问 ClpB 的两个正交功能：ATP 依赖性底物结合和底物诱导的 ATP 酶活性激活。 2. 我们将验证并确定优先级使用药物化学方法，化合物击中抑制 ClpB 的化学型。 3. 我们将验证选定的命中化合物的抑制效力，并通过进行体外测试来测试它们对 ClpB 的选择性正交生化测定的数量。 4. 我们将进行初步的抗菌活性测试革兰氏阴性菌大肠杆菌、福氏志贺氏菌和宋内志贺氏菌中的命中化合物，以及革兰氏阳性金黄色葡萄球菌。拟议研究的预期结果将是发现经验证的小分子 Hsp100 抑制剂候选物，用于未来药物化学优化和生物测试。这种方法是创新的，因为尚未实施基于伴侣的抗菌药物。