Using next generation approaches to define epidemiology and develop therapies for the neglected cystic fibrosis lung pathogen Burkholderia multivorans

使用下一代方法来定义流行病学并开发针对被忽视的囊性纤维化肺部病原体多食伯克霍尔德杆菌的治疗方法

• 批准号: 2108992
• 金额: --
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2108992
• 关键词: Using; next; generation; approaches; define

Microbial lung infection is the major cause of death in people with CF, with routine therapy often relying on continuous treatment with antibiotics. Several antimicrobial resistant (AMR) pathogens have emerged as problems in CF and transmissible Burkholderia species are one of the main causes of premature death. Epidemic spread of Burkholderia cenocepacia strains caused it to be dominant from the 1990s to early 2000s, but with infection control reducing transmission, Burkholderia multivorans has now become the most common CF Burkholderia. Unlike B. cenocepacia, the pathogenesis and the source of infection for B. multivorans remains elusive. Within the GW4, the supervisory team, EM and AB, represent a unique combination of leading expertise in CF microbiology, and they will work with bioinformaticians (TC), chemists and industry to deliver a cross-disciplinary PhD.Aim: We will fully define the pathogenesis of B. multivorans, and develop new therapeutics for infection in order to reduce premature death of people with CF. Our hypothesis is "the use of genomics and novel antibiotics isolated from other Burkholderia species will reduce lung infection."Objectives: 1. Use genomics to define the population biology and virulence of B. multivorans (Year 1). Exeter and Cardiff have excellent genomics facilities, with Cardiff also co-hosting the MRC's Cloud Infrastructure for Microbial Bioinformatics. We have extensive collections of Burkholderia, that will be combined and extended by international collaboration. A systematic panel of global B. multivorans CF and environmental strains will be assembled and genome sequenced. High resolution phylogenomic analysis will be used to fully define B. multivorans population biology, and all sequences shared online to assist global surveillance. Aim 2. Modelling the growth pathogenesis of B. multivorans in vitro and in vivo (Year 2) CF lung infection is characterised by polymicrobial communities (the CF microbiota) growing microaerobically and anaerobically within the clogged mucus. To further understand how B. multivorans grows within sputum, modelling of its low oxygen and anaerobic growth will be performed in vitro. In addition, the virulence of strains from the phylogenomic lineages identified above will be characterised using the Galleria melonella wax moth larvae infection model, in collaboration with Biosystems Technology an Exeter-based spin out. Aim 3. Developing novel therapeutic approaches for Burkholderia infection (Year 3). As part of EM's antibiotic discovery programme, the B. ambifaria antibiotic, enacyloxin IIa, has been found to have a unique activity on B. multivorans and Acinetobacter baumannii strains. The mode of action and potential for resistance of B. multvorans will be investigated using mutant re-sequencing and transcriptomics.

微生物肺部感染是CF患者死亡的主要原因，常规治疗通常依赖于抗生素的持续治疗。几种抗生素耐药（AMR）病原体已成为CF中的问题，而可传播的伯克霍尔德菌属是过早死亡的主要原因之一。新洋葱伯克霍尔德菌菌株的流行性传播导致其在20世纪90年代至21世纪初占主导地位，但随着感染控制减少传播，多食伯克霍尔德菌现已成为最常见的CF伯克霍尔德菌。不像B。B.多栖动物仍然难以捉摸。在GW4中，管理团队EM和AB代表了CF微生物学领先专业知识的独特组合，他们将与生物信息学家（TC），化学家和工业界合作，提供跨学科的博士学位。多食动物，并开发新的感染治疗方法，以减少CF患者的过早死亡。我们的假设是“使用基因组学和从其他伯克霍尔德菌属物种中分离出的新型抗生素将减少肺部感染。“目标：使用基因组学来定义B的种群生物学和毒力。多栖动物（1年级）。埃克塞特和卡迪夫拥有出色的基因组学设施，卡迪夫还共同主持了MRC的微生物生物信息学云基础设施。我们有广泛的伯克霍尔德菌，将通过国际合作进行合并和扩展。全球B的系统面板。将组装多噬菌体CF和环境菌株并进行基因组测序。将使用高分辨率PCR基因组分析来完全定义B。多鸟种群生物学，以及所有在线共享的序列，以协助全球监测。目标2.模拟B的生长发病机制。CF肺部感染的特征在于在堵塞的粘液中以微需氧和厌氧方式生长的多微生物群落（CF微生物群）。进一步了解B.多噬菌体在痰液中生长，将在体外对其低氧和厌氧生长进行建模。此外，将与Biosystems Technology（基于Exeter的衍生物）合作，使用Galleria melonella wax moth幼虫感染模型对上述鉴定的大肠杆菌基因组谱系菌株的毒力进行表征。目标3.开发新的治疗方法伯克霍尔德菌感染（3年）。作为EM抗生素发现计划的一部分，B.已发现ambifaria抗生素enacloxin IIa对B具有独特的活性。多噬菌和鲍氏不动杆菌菌株。B的作用方式和耐药潜力。将使用突变体重测序和转录组学研究多噬菌体。