HTS for copper-activated inhibitors against MRSA

用于抗 MRSA 的铜激活抑制剂的 HTS

• 批准号: 9177088
• 负责人: Frank Wolschendorf
• 金额: $ 82.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177088
• 关键词: Affinity; Anti-Bacterial Agents; Antibiotics; Antineoplastic Agents; Bacteria; Bacterial Infections; Binding; Biochemical; Biological; Biological Assay; Bypass; Cells; Cessation of life; Characteristics; Chemicals; Chemistry; Collaborations; Collection; Communicable Diseases; Complement; Complex; Copper; Data; Development; Drug Combinations; Drug Kinetics; Drug Targeting; Drug resistance; Eukaryotic Cell; Family; Family Study; Goals; Homeostasis; Human; In Vitro; Investigation; Ions; Laboratories; Libraries; Ligands; Mediating; Metals; Microbial Biofilms; Microbial Drug Resistance; Miniaturization; Molecular; Nitrogen; Oxygen; Patients; Physiological; Property; Public Health; Publishing; Research; Resistance; Specificity; Staphylococcus aureus; Structure; Structure-Activity Relationship; Sulfur; Techniques; Therapeutic; Toxic effect; Translating; Vaccines; Work; antimicrobial; base; biological systems; combat; design; drug development; drug discovery; drug resistant bacteria; functional group; high throughput screening; inhibitor/antagonist; metal complex; methicillin resistant Staphylococcus aureus; novel; novel therapeutics; pathogen; pharmacophore; programs; resistance frequency; respiratory; response; scaffold; screening; small molecule; small molecule libraries; success

PROJECT SUMMARY Methicillin-resistant Staphylococcus aureus (MRSA) is a dangerous drug-resistant pathogen. The death toll due to S. aureus is the second highest amongst patients infected with nosocomial drug-resistant bacteria. In the absence of a vaccine, antibiotics are the most effective solution to pharmacologically combat bacterial infections. However, the discovery of novel drugs capable of bypassing microbial drug resistance is a formidable and complex challenge. Amongst promising concepts for drug discovery and development is the use of copper. Free copper ions lack therapeutic properties but, if coordinated to small molecules, can bestow antimicrobial activity to the ensuing complex. These complexes can mediate target directed attacks. Recently, copper/ligand complexes with potentially exploitable antibacterial properties have emerged from our and other laboratories, but the concept has not yet been systematically translated into high-throughput drug discovery screening. According to our exploratory proof-of-principle screen on S. aureus, compounds with copper-dependent activities are not rare, but the insufficient copper content of commonly used screening media prohibited their discovery during high-throughput screening (HTS) in the past. Therefore, we propose to incorporate a copper-activation component in drug discovery screens so that a greater repertoire of bioactivities within existing libraries becomes available. Our preliminary data suggest that novel and previously undetectable antimicrobials are readily discovered through application of this concept. In collaboration with Southern Research, a world renowned not- for-profit center for HTS and drug development, we propose to establish a discovery and development pipeline for copper-related bacterial inhibitors. For that purpose, we will conduct a pilot screen to demonstrate the utility and specificity of our novel primary screening assay (AIM1) and the quality of novel probes for potential improvement and advancement towards medicinal applications (AIM2). Finally, we propose to perform mode of action studies, investigate biological responses and detail mechanisms of metal-ligand interactions (AIM3) at both the cellular and the molecular level.

项目摘要 耐甲氧西林金黄色葡萄球菌（MRSA）是一种危险的耐药病原体。死亡人数 对鼠伤寒沙门氏金黄色葡萄球菌是感染医院耐药细菌的患者中第二高的。在 在没有疫苗的情况下，抗生素是对抗细菌感染的最有效方法。 然而，能够绕过微生物耐药性的新型药物的发现是一项艰巨的任务， 复杂的挑战。铜的使用是药物发现和开发的一个有前途的概念。免费 铜离子缺乏治疗特性，但如果与小分子配位，则可以赋予抗微生物活性 到随后的复杂。这些复合物可以介导靶向攻击。最近，铜/配体 具有潜在可开发的抗菌性能的复合物已经从我们和其他实验室中出现， 但是该概念还没有被系统地转化为高通量药物发现筛选。 根据我们在S.金黄色葡萄球菌，具有铜依赖活性的化合物 并不罕见，但通常使用的筛选介质中铜含量不足，阻止了它们的发现 在过去的高通量筛选（HTS）中。因此，我们建议将铜活化 药物发现筛选中的一个组成部分，以便现有文库中的生物活性的更大库成为 available.我们的初步数据表明，新的和以前检测不到的抗菌剂很容易 通过这个概念的应用。与南方研究合作，一个世界知名的非- 作为HTS和药物开发的营利性中心，我们建议建立一个发现和开发管道 铜相关的细菌抑制剂为此，我们将进行一个试点屏幕，以展示实用程序 和特异性，我们的新的初步筛选试验（AIM 1）和新的探针的质量，为潜在的 医学应用的改进和进步（AIM 2）。最后，我们建议执行模式 行动研究，研究生物反应和金属配体相互作用（AIM 3）的详细机制， 细胞和分子水平上的。