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.

抗菌素耐药性 (AMR) 是一个新出现的问题，如果不加以控制，到 2050 年，造成的死亡人数将超过癌症。制定新策略来缓解这一问题是全球健康的一项重要优先事项。一个重要的并发症是医院感染中出现抗生素耐药性机会致病菌。其中，肺炎克雷伯菌是最紧迫的问题之一，其地理传播迅速且碳青霉烯类耐药性不断增强。这是最后一线抗生素，因此这种耐药性对于弱势患者群体的治疗来说是一个真正的问题。鉴于这种背景，开发基于（细菌）噬菌体的治疗方法，特别是那些探索噬菌体-抗生素协同作用的方法，是一个有吸引力的研究途径。我们的团队具有独特的优势，可以测试这种方法针对克雷伯氏菌的靶向、减轻和显示选择性毒性的可行性。南卡罗来纳大学研究小组已经开发出识别针对抗生素耐药克雷伯氏菌的噬菌体物种的方法。他们将与 UKHSA 的同事合作，扩展这项研究，以对最有效地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。该方法将允许多重分析和比较方法来了解噬菌体和噬菌体抗生素作用的机制。南卡罗来纳大学和 UKHSA 之前的合作工作建立了遗传易驯化的生物体秀丽隐杆线虫作为克雷伯氏菌发病机制的优秀模型。这产生了强有力的措施来分析和区分 UKHSA 策划的一系列临床相关克雷伯氏菌菌株的致病性。这将用于研究噬菌体/噬菌体抗生素对非目标生物体的毒性，作为高等生物体后续开发的引物。定量分析将使我们能够研究克雷伯氏菌定植之前和之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，需要理解。这可以通过使用线虫突变体来详细说明，这些突变体定义了可能受到噬菌体、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。总体而言，该项目将提供关键卫生优先领域抗菌素耐药性的关键培训。其总体目标是确定一类关键抗生素耐药感染的机制和治疗方法。