Antibiotic targeting of protein interfaces in bacterial genome maintenance comple

细菌基因组维护复合物中蛋白质界面的抗生素靶向

基本信息

批准号：
9222869
负责人：
James L Keck
金额：
$ 44.73万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2016-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222869
关键词：
Active Sites Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial DNA Bacterial Genome Bacterial Infections Binding Binding Sites Biochemical Biological Assay C-terminal Cell Death Cell Survival Cell physiology Cells Chemicals Clinical Complex Computer Simulation Coupled Cytoplasm DNA Primase DNA biosynthesis Development Drug resistance Enzymes Escherichia coli Explosion Fibrinogen Fluorescence Anisotropy Fluorescence Microscopy Fluoroquinolones Future Genome Health In Vitro Industry Infection Klebsiella pneumonia bacterium Knowledge Lead Libraries Link Maintenance Maps Measures Mediating Medical Methods Molecular Nature Pharmacologic Substance Phase Positioning Attribute Proteins Public Health Replication-Associated Process Research Rewards SS DNA BP Site Structure System Testing Therapeutic Time base chemical reaction combat drug development drug discovery effective therapy experience helicase high throughput screening in vivo Model inhibitor/antagonist innovation novel novel strategies pathogen protein complex research study screening small molecule small molecule inhibitor stem success therapeutic target virtual

项目摘要

DESCRIPTION (provided by applicant): The emergence of antibiotic-resistant bacteria coupled with the dwindling supply of new antibacterial therapeutics has created a medical crisis. Traditional industry-driven approaches that target the active sites of essential enzymes have begun to stall, yielding fewer new antibacterial agents than are needed to combat the alarming wave of drug-resistant pathogens that have become commonplace in clinical settings. Novel approaches to therapeutic discovery are essential for generating effective treatments against emerging bacterial threats. This application tests the utility of protein interfaces, rather than enzyme active sites, as targets for antibacterial drug development. This mode of action takes advantage of the essential nature of protein interactions in supporting cellular processes, which are underexplored therapeutic targets. With its many essential protein interactions, the bacterial DNA replication machinery is an ideal system that will be used to test the robustness of protein interfaces as antibacterial therapeutic targets. High-throughput screens will identify compounds that disrupt bacterial DNA replication protein complexes and the mechanisms of action of the compounds will be determined using a combination of structural, biochemical and cellular studies. Antibiotic activities of the compounds will be assessed with a broad spectrum of bacterial species. The proposed approach will simultaneously test the extent to which protein interfaces can be used for antibacterial drug development and the suitability of DNA replication protein complexes as direct targets for such inhibitors. The rewards of this proposed research could pave the way to much needed antibacterial lead compounds and establish protein interfaces as novel targets for antibacterial drug development.

描述（由申请人提供）：抗生素耐药菌的出现，加上新的抗菌治疗剂的供应量减少，造成了医疗危机。针对基本酶主动部位的传统行业驱动的方法已经开始停滞，产生的新抗菌剂少于抵抗在临床环境中普遍存在的令人震惊的耐药病原体浪潮所需的。治疗发现的新颖方法对于为针对新兴细菌威胁而产生有效的治疗方法至关重要。该应用测试了蛋白质界面的实用性，而不是酶的活性位点，作为抗菌药物开发的靶标。这种作用方式利用了支持细胞过程中蛋白质相互作用的基本性质，而细胞过程是毫无疑问的治疗靶标。细菌DNA复制机制具有许多必不可少的蛋白质相互作用，是一个理想的系统，可用于测试蛋白质界面作为抗菌治疗靶标的鲁棒性。高通量筛选将鉴定破坏细菌DNA复制蛋白复合物的化合物，并使用结构，生化和细胞研究的结合确定化合物的作用机制。该化合物的抗生素活性将通过各种细菌物种进行评估。所提出的方法将同时测试蛋白质界面可用于抗菌药物发育的程度，以及DNA复制蛋白复合物作为此类抑制剂的直接靶标。这项提出的研究的回报可以为急需的抗菌铅化合物铺平道路，并建立蛋白质界面作为抗菌药物开发的新靶标。