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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：
9240583
负责人：
James L Keck
金额：
$ 44.63万
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/9240583
关键词：
Active Sites Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Antibiotic Resistance Bacterial DNA Bacterial Genome Bacterial Infections Binding Binding Proteins Binding Sites Biochemical Biological Assay C-terminal Cell Death Cell Survival Cell physiology Cells Chemicals Clinical Complex Computer Simulation Coupled Crystallization Cytoplasm DNA Primase DNA biosynthesis Development DnaG Protein Drug resistance Enzymes Escherichia coli Explosion Fibrinogen Fluorescence Anisotropy Fluorescence Microscopy Fluoroquinolones Future Genome 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 bacterial resistance base chemical reaction combat drug development drug discovery effective therapy experience experimental study helicase high throughput screening in vivo Model inhibitor/antagonist innovation novel novel strategies pathogen protein complex protein protein interaction public health relevance 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(申请人提供)：抗生素抗药性细菌的出现，加上新的抗菌疗法供应的减少，造成了一场医疗危机。针对关键酶活性部位的传统行业驱动的方法已经开始停滞不前，产生的新抗菌剂少于对抗令人震惊的耐药病原体浪潮所需的药物，这些病原体已在临床环境中变得司空见惯。治疗发现的新方法对于产生针对新出现的细菌威胁的有效治疗至关重要。这项应用测试了作为抗菌药物开发目标的蛋白质界面而不是酶活性部位的效用。这种作用模式利用了蛋白质相互作用在支持细胞过程中的基本性质，而细胞过程是未被探索的治疗靶点。细菌DNA复制机制具有许多基本的蛋白质相互作用，是一个理想的系统，将被用于测试作为抗菌治疗靶点的蛋白质界面的稳定性。高通量筛选将识别破坏细菌DNA复制蛋白复合体的化合物，这些化合物的作用机制将结合结构、生化和细胞研究来确定。这些化合物的抗菌活性将通过广泛的细菌种类进行评估。建议的方法将同时测试蛋白质界面可用于抗菌药物开发的程度，以及DNA复制蛋白质复合体是否适合作为此类抑制剂的直接靶点。这项拟议研究的成果可能为开发急需的抗菌先导化合物铺平道路，并建立蛋白质界面作为抗菌药物开发的新靶点。