Antibiotic targeting of protein interfaces in bacterial genome maintenance comple

描述（由申请人提供）：抗生素耐药细菌的出现，加上新的抗菌药物供应的减少，造成了一场医疗危机。传统的工业驱动的方法，以必需酶的活性位点为目标，已经开始停滞不前，产生的新的抗菌剂比对抗临床环境中司空见惯的令人担忧的耐药病原体所需的还要少。新的治疗方法对于产生有效的治疗方法来对抗新出现的细菌威胁是必不可少的。这个应用测试了蛋白质界面的效用，而不是酶活性位点，作为抗菌药物开发的目标。这种作用模式利用了支持细胞过程的蛋白质相互作用的本质，这是尚未开发的治疗靶点。细菌DNA复制机制具有许多必需的蛋白质相互作用，是一个理想的系统，将用于测试作为抗菌治疗靶点的蛋白质界面的稳健性。高通量筛选将识别破坏细菌DNA复制蛋白复合物的化合物，并将使用结构、生化和细胞研究相结合的方法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复制蛋白复合物作为此类抑制剂的直接靶点的适用性。这项研究的回报可能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。

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.