Identifying Robust Collateral Sensitivity Phenotypes Exploitable in a Clinical Context to Minimise the Emergence of Antimicrobial Resistance

T1基础研究- T2临床研究抗菌素耐药性（AMR）对全球健康构成重大威胁。迫切需要限制AMR出现的新策略。一种有希望的方法涉及利用进化生物学，特别是一种被称为附带敏感性的现象，即对一类抗生素的敏感性的变化可能是由于突变导致对不相关抗生素的耐药性。通过利用顺序抗生素治疗来选择抵抗性，可以利用与抗生素抗性突变的保存相关的权衡。为了使超敏表型可转移到临床环境中，必须在不同的细菌菌株和遗传背景中建立其重现性和保守性。然而，现有的研究主要集中在单一生长条件下使用多种抗生素进化单一菌株，在不同菌株和条件下的附带敏感性网络的稳健性方面存在知识空白。该项目旨在通过确定1）导致细菌沿着与我们在体内观察到的相同进化途径进化为耐药性的实验室培养基，以及2）在不同菌株和基因组背景中可重现的强大的附带敏感性网络来解决这一差距。通过包括适应性实验室进化、敏感性测试、适应性评估和详细的生物信息学分析的综合方法，潜在的结果包括鉴定可以顺序和互换使用的抗生素对，以增加细菌对其他抗生素的敏感性，特别关注耐碳青霉烯类、产ESBL的肠杆菌科。对进化轨迹有更全面的了解将有助于制定对抗AMR的策略，并通过允许临床医生使用经过验证的抗生素治疗来改善患者的预后，从而最大限度地减少耐药性的出现。

T1 Basic Research - T2 Clinical ResearchAntimicrobial resistance (AMR) poses a significant threat to global health. Novel strategies in limiting the emergence of AMR are critically needed. One promising approach involves the exploitation of evolutionary biology, specifically a phenomenon known as collateral sensitivity, whereby changes in sensitivity to one class of antibiotics may occur as a result of mutations leading to resistance to an unrelated class of antibiotics. By utilising sequential antibiotic treatment to select against resistance, trade-offs associated with the preservation of antibiotic resistance mutations can be exploited. For a hypersensitive phenotype to be transferable to a clinical setting, it is imperative to establish its reproducibility and conservation across diverse bacterial strains and genetic backgrounds. However, existing studies have predominantly focused on evolving single strains with multiple antibiotics under single growth conditions, leaving a knowledge gap regarding the robustness of collateral sensitivity networks across different strains and conditions. This project aims to address this gap by identifying 1) laboratory media that results in bacteria evolving to resistance along the same evolutionary pathways as we observe in vivo, and 2) robust collateral sensitivity networks reproducible in different strains and genomic backgrounds. Through a comprehensive approach encompassing adaptive laboratory evolution, susceptibility testing, fitness assessment, and detailed bioinformatic analysis, the potential outcomes include the identification of antibiotic pairs that can be sequentially and interchangeably employed to increase bacterial sensitivity to other antibiotics, with a specific focus on carbapenem-resistant, ESBL-producing Enterobacteriaceae. Gaining a more comprehensive understanding of evolutionary trajectories will inform the development of strategies to combat AMR and improve patient outcomes by allowing clinicians to use proven antibiotic therapy which minimises the emergence of resistance.