Mechanisms of antimicrobial resistance in Helicobacter pylori

幽门螺杆菌耐药机制

• 批准号: 2746397
• 金额: --
• 依托单位: Nottingham Trent University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2746397
• 关键词: Mechanisms; antimicrobial; resistance; Helicobacter; pylori

Helicobacter pylori is a Gram negative, microaerophilic bacterium that infects the human stomach and causes peptic ulcers and gastric cancer. It is a bacterial class I carcinogen and is one of the leading causes of preventable cancer deaths worldwide. Treatment of H. pylori infection is becoming increasingly difficult due to the emergence of antibiotic resistance, and about 20% of first line H. pylori treatments now fail to eradicate the bacteria from the stomach. The World Health Organisation recently named clarithromycin resistant H. pylori as one of the highest priority antibiotic resistant pathogens for which new treatments are needed.H. pylori is a highly polymorphic bacterium, with high mutation and recombination rates. There are high levels of variation in H. pylori genome sequences across the world and even variation in H. pylori genotypes within individual patients' stomachs. H. pylori is not routinely cultured from infected patients for antibiotic susceptibility testing because it can only be recovered via an invasive procedure (endoscopy) and it is a slow-growing, fastidious organism. There is a need for more research into the antibiotic susceptibility profiles of currently circulating H. pylori strains. Research linking genotype to phenotype would be particularly beneficial because it would allow us to better understand how H. pylori becomes antibiotic resistant. This information could be used in the future to help develop new non-invasive diagnostic tests to inform treatment, and new treatments.This PhD project would include some or all of the following:- Antibiotic susceptibility testing of H. pylori isolates from human clinical cases and comparison of phenotype to genotype using whole genome sequence analysis.- Directed evolution experiments in which we would expose H. pylori to antibiotics in the lab and isolate any colonies that became resistant. Genome sequence and complete comparative genomics analyses would then determine the mechanisms of the resistance that has developed.- Molecular modelling experiments using genomic data to predict mechanisms of antibiotic resistance.- Nanopore MinION sequencing of H. pylori isolates then combination of this data with our existing Illumina MiSeq short read data to produce high quality, complete hybrid genome assemblies. These could then be used to study the antibiotic resistance genes of H. pylori in more detail, including plasmid analysis.

幽门螺杆菌是一种革兰氏阴性的微嗜气细菌，感染人的胃并引起消化性溃疡和胃癌。它是一类细菌致癌物，是全球可预防癌症死亡的主要原因之一。由于抗生素耐药性的出现，幽门螺杆菌感染的治疗变得越来越困难，现在大约20%的幽门螺杆菌一线治疗无法从胃中根除细菌。世界卫生组织最近将耐克拉霉素的幽门螺杆菌列为需要新疗法的最优先抗生素耐药病原体之一。幽门螺杆菌是一种高度多态性的细菌，具有很高的突变和重组率。世界各地的幽门螺杆菌基因组序列差异很大，甚至在个别患者的胃中也存在幽门螺杆菌基因型差异。由于幽门螺杆菌只能通过侵入性手术（内窥镜检查）才能恢复，而且它是一种生长缓慢、挑剔的微生物，因此不能常规地从感染患者身上培养幽门螺杆菌进行抗生素敏感性试验。有必要对目前流行的幽门螺杆菌菌株的抗生素敏感性进行更多的研究。将基因型与表型联系起来的研究将特别有益，因为它将使我们更好地了解幽门螺杆菌是如何产生抗生素耐药性的。这些信息可以在未来用于帮助开发新的非侵入性诊断测试，以告知治疗和新的治疗方法。该博士项目将包括以下部分或全部内容：-人类临床病例幽门螺杆菌分离株的抗生素敏感性测试，并使用全基因组序列分析进行表型与基因型的比较。-定向进化实验，我们将幽门螺杆菌暴露在实验室的抗生素中，并分离出任何产生耐药性的菌落。基因组序列和完整的比较基因组分析将确定产生耐药性的机制。-利用基因组数据进行分子模拟实验，预测抗生素耐药性机制。-幽门螺杆菌分离物的纳米孔MinION测序，然后将这些数据与我们现有的Illumina MiSeq短读数据相结合，以产生高质量，完整的杂交基因组组装。这些可以用于更详细地研究幽门螺杆菌的抗生素抗性基因，包括质粒分析。