Phage mitigation of Klebsiella infection: a new approach for AMR

噬菌体缓解克雷伯氏菌感染：AMR 的新方法

• 批准号: 2881519
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2881519
• 关键词: Phage; mitigation; Klebsiella; infection; new

Antimicrobial resistance (AMR) is an emerging problem which left unchecked will cause more deaths than cancer by 2050. Developing new strategies to mitigate this is an important worldwide health priority. An important complication is the emergence of antibiotic-resistant opportunistic pathogens underlying nosocomial infections. Among these, Klebsiella pneumoniae is one of the most pressing concerns, with rapid geographical spread and growing carbapenem resistance. This is the last line antibiotic so such resistance is a real issue for the treatment of a vulnerable patient cohort. Given this background, developing (bacterio)phage-based therapeutic approaches, especially those exploring phage-antibiotic synergies, is an attractive avenue of investigation. Our team is uniquely placed to test the feasibility of this approach to target, mitigate and show selective toxicity on Klebsiella. The UofS group has developed approaches to identify phage species that target antibiotic-resistant Klebsiella. In collaboration with colleagues at UKHSA, they will extend this investigation to score phage or phage-antibiotic combinations that most efficaciously disrupt Klebsiella strains. The approach will allow multiplexing and a comparative approach to inform on the mechanism of phage and phage-antibiotic action. Previous collaborative work from UofS and UKHSA established the genetically-tractable organism C. elegans as an excellent model for Klebsiella pathogenesis. This generates robust measures to profile and differentiate pathogenicity for a range of clinically-relevant Klebsiella strains curated at UKHSA. This will be used to investigate toxicity of phage/phage-antibiotic on a non-target organism to act as a primer for subsequent development in higher organisms. The quantitative assays will allow us to investigate phage mitigation of pathogenesis prior to, and upon Klebsiella colonization. Furthermore, there is an obvious context of trophic interaction between phage, bacteria and bacterial host that needs to be understood. This can be detailed through use of C. elegans mutants that define the molecular determinants of host biology that might be impacted by phage, bacteria or phage-infected bacteria. Overall this project will provide critical training in the key health priority area AMR. Its overall goal aims to define mechanisms and treatment for a key class of antibiotic-resistant infections.

抗生素耐药性（AMR）是一个新出现的问题，到2050年，如果不加以控制，将导致比癌症更多的死亡。制定新的战略来缓解这一问题是一个重要的全球卫生优先事项。一个重要的并发症是出现耐药的机会致病菌的医院感染。其中，肺炎克雷伯菌是最紧迫的问题之一，具有快速的地理传播和日益增长的碳青霉烯耐药性。这是最后一线抗生素，因此这种耐药性是治疗脆弱患者队列的真实的问题。在这种背景下，开发（细菌）噬菌体为基础的治疗方法，特别是那些探索噬菌体抗生素协同作用，是一个有吸引力的研究途径。我们的团队处于独特的位置，可以测试这种方法的可行性，以靶向，减轻和显示对克雷伯氏菌的选择性毒性。UofS小组已经开发出鉴定靶向耐药克雷伯氏菌的噬菌体种类的方法。他们将与UKHSA的同事合作，将这项研究扩展到对最有效破坏克雷伯氏菌菌株的噬菌体或噬菌体-抗生素组合进行评分。该方法将允许多路复用和比较方法，以告知噬菌体和噬菌体-抗生素作用的机制。UofS和UKHSA先前的合作工作建立了遗传上易处理的生物体C。线虫作为克雷伯氏菌致病机理的极好模型。这产生了强有力的措施，以分析和区分在UKHSA管理的一系列临床相关克雷伯菌菌株的致病性。这将用于研究噬菌体/噬菌体-抗生素对非靶生物的毒性，以作为随后在高等生物中开发的引物。定量测定将使我们能够研究克雷伯氏菌定殖前和定殖后噬菌体对发病机制的缓解作用。此外，噬菌体、细菌和细菌宿主之间存在明显的营养相互作用背景，需要理解。这可以通过使用C来实现。线虫突变体，其定义了可能受噬菌体、细菌或噬菌体感染的细菌影响的宿主生物学的分子决定因素。总的来说，该项目将提供关键卫生优先领域AMR的关键培训。其总体目标旨在确定一个关键类别的耐药性感染的机制和治疗。