Antibiotic targeting of protein interfaces in bacterial genome maintenance comple

摘要 抗药性细菌的出现加上新抗菌药物的供应减少 治疗学已经造成了医学危机。传统的行业驱动的方法，目标是活跃的网站， 必需的酶已经开始停滞，产生的新的抗菌剂比对抗细菌所需的要少。 令人震惊的耐药病原体浪潮已经成为临床环境中的常见现象。小说 治疗发现的方法对于产生有效的治疗方法是必不可少的， 细菌威胁这个建议测试的效用蛋白质接口，而不是酶的活性位点，作为目标 用于抗菌药物的开发。这种作用方式利用了蛋白质的基本性质 在支持细胞过程中的相互作用，这是探索不足的治疗靶点。拥有众多 细菌DNA复制机制是一个理想的系统，将用于 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复制蛋白质复合物的化合物和 将使用结构、生物化学和细胞研究的组合来确定化合物。 将用广谱细菌物种评估化合物的抗生素活性。的 所提出的方法将同时测试蛋白质界面可用于抗菌的程度。 药物开发和DNA复制蛋白复合物作为此类抑制剂的直接靶点的适用性。 这项拟议中的研究的回报可以为急需的抗菌先导化合物铺平道路， 建立蛋白质界面作为抗菌药物开发的新靶点。

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.