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

项目概述：这个mrc资助的博士培训合作伙伴关系（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起来，使学生能够在与行业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，第一年包括一系列教学模块和两个基于实验室的研究项目，最终获得跨学科生物医学研究硕士学位。前两个学期包括一系列教学模块，让学生在多学科科学方面打下坚实的基础。学生还将参加一系列由分子、细胞和组织动力学、微生物学和感染、应用生物医学技术、人工智能和数据科学等领域的学术和行业专家主持的大师班。在第三学期和夏季学期，学生在他们选择的实验室进行两个为期11周的研究项目。项目概述：发现针对耐药革兰氏阴性菌的新型抗菌药物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良好靶点。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座酶MraY，并确定了转座酶MraY与噬菌体X174的裂解蛋白E之间的蛋白质-蛋白质相互作用位点。该位点可以被模拟Arg-Trp-x-x-Trp基序的肽靶向，这些肽对革兰氏阴性细菌（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（拟肽物）的化学合成和生物学测试，这些化合物可能具有更好的候选药物性能。化合物将作为MraY抑制剂使用体外实验室测定进行测试，并将评估其对一系列细菌菌株（包括耐药菌株）的抗菌活性。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），以完善抑制剂结构，活性化合物将在铜绿假单胞菌感染模型中进行测试。该项目将涉及候选药物的化学合成、酶纯化和定量酶分析、计算药物设计以及针对临床相关抗生素耐药菌株的抗菌测试等跨学科培训。

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.