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

• 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
• 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

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）：抗生素耐药细菌的出现，加上新抗菌疗法供应的减少，造成了一场医疗危机。针对必需酶活性位点的传统行业驱动方法已开始停滞，产生的新型抗菌药物少于对抗临床环境中已司空见惯的令人震惊的耐药病原体浪潮所需的药物。治疗发现的新方法对于针对新出现的细菌威胁产生有效的治疗方法至关重要。该应用测试了蛋白质界面（而不是酶活性位点）作为抗菌药物开发目标的效用。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本质，这是尚未充分探索的治疗靶点。细菌 DNA 复制机制具有许多重要的蛋白质相互作用，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点的稳健性。高通量筛选将鉴定破坏细菌 DNA 复制蛋白复合物的化合物，并结合结构、生化和细胞研究确定这些化合物的作用机制。这些化合物的抗生素活性将通过广泛的细菌种类进行评估。所提出的方法将同时测试蛋白质界面可用于抗菌药物开发的程度以及DNA复制蛋白质复合物作为此类抑制剂的直接靶标的适用性。这项拟议研究的回报可以为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。