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：
8703312
负责人：
David R Andes
金额：
$ 22.17万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703312
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 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 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 public health relevance research study screening small molecule stem success therapeutic target virtual

项目摘要

Abstract 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 proposal 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.

抽象的抗生素耐药菌的出现以及新抗菌的供应减少治疗剂造成了医疗危机。传统行业驱动的方法针对的是必需酶已经开始停滞，产生的新抗菌剂少于对抗在临床环境中司空见惯的抗药性病原体的令人震惊的浪潮。小说治疗发现方法对于产生有效的治疗方法至关重要细菌威胁。该建议测试蛋白质界面的实用性，而不是酶的活性位点，作为目标用于抗菌药物开发。这种作用方式利用蛋白质的基本性质支持细胞过程中的相互作用，这些过程是未经置换的治疗靶标。有很多必需蛋白质相互作用，细菌DNA复制机制是一种理想的系统，将用于测试蛋白质界面作为抗菌治疗靶标的鲁棒性。高通量屏幕将确定破坏细菌DNA复制蛋白复合物的化合物和作用机理这些化合物将使用结构，生化和细胞研究的组合确定。该化合物的抗生素活性将通过各种细菌物种进行评估。这提出的方法将同时测试可以将蛋白质界面用于抗菌的程度药物开发和DNA复制蛋白复合物作为此类抑制剂的直接靶标。这项拟议的研究的回报可以为急需的抗菌铅化合物铺平道路建立蛋白质界面作为抗菌药物开发的新靶标。