Inhibitors for the interaction site between translocase MraY and the lysis protein E from bacteriophage X174 as anti-Pseudomonas therapeutics

易位酶 MraY 和噬菌体 X174 裂解蛋白 E 之间相互作用位点的抑制剂作为抗假单胞菌疗法

• 批准号: 2269737
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2269737
• 关键词: Inhibitors; interaction; site; between; translocase

Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address important applied biomedical research questions in priority areas aligned with industry. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project overview:The discovery of novel antimicrobial agents against antibiotic-resistant Gram-negative bacteria is an important clinical need, to combat growing antibiotic resistance and shortage of new therapies. Assembly of the bacterial cell wall peptidoglycan is a well-proven target for antibacterial action, by penicillins and glycopeptide antibiotics. Professor Bugg's research group has previously studied translocase enzyme MraY on the bacterial cell wall peptidoglycan biosynthetic pathway, and has identified a protein-protein interaction site between translocase enzyme MraY and lysis protein E from bacteriophage X174. This site can be targeted by peptides mimicking a motif Arg-Trp-x-x-Trp, which show antimicrobial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli.The project will involve the chemical synthesis and biological testing of non-peptide compounds (peptidomimetics) that target this site, which are likely to have better properties as drug candidates. Compounds will be tested as MraY inhibitors using in vitro laboratory assays, and will be evaluated for antimicrobial activity against a range of bacterial strains, including antibiotic-resistant strains. The crystal structure of MraY will be used to carry out structure-based drug design (with industrial partner LifeArc), to refine inhibitor structures, and active compounds will be tested in Pseudomonas aeruginosa infection models. The project will involve interdisciplinary training in chemical synthesis of drug candidates, enzyme purification and quantitative enzyme assays, computational drug design, and antimicrobial testing against clinically relevant antibiotic-resistant bacterial strains.

课程概述：这个由MRC资助的博士培训伙伴关系(DTP)将尖端的分子和分析科学与数据分析中的创新计算方法结合在一起，使学生能够在与行业保持一致的优先领域解决重要的应用生物医学研究问题。这是一个为期4年的课程，第一年包括一系列的教学模块和两个基于实验室的研究项目，这些项目导致了跨学科生物医学研究的硕士学位。前两个学期包括精选的教学模块，使学生能够在多学科的科学中获得坚实的基础。学生们还参加了由学术和行业专家主持的一系列大师课程，这些专家涉及分子、细胞和组织动力学、微生物学和传染病、应用生物医学技术以及人工智能和数据科学等领域。在第三学期和暑期，学生们在他们选择的实验室里进行两个为期十一周的研究项目。项目概述：针对耐药革兰氏阴性菌的新型抗菌剂的发现是一项重要的临床需求，以应对日益增长的抗生素耐药性和新疗法的短缺。细菌细胞壁肽聚糖的组装是青霉素类和糖肽类抗生素抗菌作用的有效靶点。Bugg教授的研究小组此前研究了细菌细胞壁肽聚糖生物合成途径上的转位酶mray，并确定了转位酶mray与来自噬菌体x174的裂解蛋白E之间的蛋白质-蛋白质相互作用位点。这个位点可以通过模拟Arg-Trp-x-x-Trp基序的多肽来靶向，该基序对革兰氏阴性菌如铜绿假单胞菌和大肠杆菌具有抗菌活性。该项目将涉及针对该位点的非肽化合物(肽仿制)的化学合成和生物学测试，这些化合物作为候选药物可能具有更好的性能。化合物将作为mray抑制剂使用体外实验室测试，并将评估对一系列细菌菌株的抗菌活性，包括抗生素耐药菌株。Mray的晶体结构将用于进行基于结构的药物设计(与工业合作伙伴LifeArc)，以优化抑制剂结构，并将在铜绿假单胞菌感染模型中测试活性化合物。该项目将涉及候选药物的化学合成、酶纯化和定量酶分析、计算机药物设计以及针对临床相关耐药细菌菌株的抗菌素测试方面的跨学科培训。