Phage mitigation of Klebsiella infection: a new approach for AMR

抗菌素耐药性(AMR)是一个新出现的问题，到2050年，如果不加以控制，导致的死亡人数将超过癌症。制定缓解这一问题的新战略是一项重要的全球卫生优先事项。一个重要的并发症是医院感染背后的抗药性机会性病原体的出现。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。这是最后一种抗生素，因此这种耐药性对于脆弱患者队列的治疗来说是一个真正的问题。在这种背景下，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。我们的团队处于独特的地位，可以测试这种方法的可行性，以靶向、缓解和显示对克雷伯氏菌的选择性毒性。UofS小组已经开发出识别针对抗药性克雷伯氏菌的噬菌体物种的方法。与UKHSA的同事合作，他们将扩大这项调查，以评分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。这种方法将允许多重和比较的方法，以告知噬菌体和噬菌体-抗生素作用的机制。UofS和UKHSA之前的合作工作建立了遗传易驯化的生物秀丽线虫作为克雷伯氏菌致病的优秀模型。这产生了强有力的措施，以描述和区分一系列临床相关的克雷伯氏菌菌株在UKHSA的致病性。这将被用来研究噬菌体/噬菌体抗生素对非目标生物体的毒性，以作为在高等生物体中后续开发的引子。定量分析将使我们能够研究在克雷伯氏菌定植之前和之后噬菌体对致病作用的缓解。此外，还需要了解噬菌体、细菌和细菌宿主之间的营养相互作用的明显背景。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、细菌或受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，该项目将在关键的卫生优先领域AMR提供关键培训。其总体目标是确定一类关键的抗生素耐药感染的机制和治疗方法。

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.