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。迫切需要新的策略来限制AMR的出现。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，根据这种现象，对一种抗生素的敏感性可能会因为突变而导致对一种无关的抗生素产生抗药性。通过使用连续的抗生素治疗来选择耐药性，可以利用与保存抗生素耐药性突变相关的权衡。为了将一种超敏表型转移到临床环境中，必须建立其在不同细菌菌株和遗传背景下的重复性和保守性。然而，现有的研究主要集中在单一生长条件下进化出具有多种抗生素的单一菌株，这就留下了一个关于不同菌株和条件下侧支敏感性网络的稳健性的知识空白。该项目旨在通过确定1)导致细菌沿着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介质，以及2)可在不同菌株和基因组背景中复制的强大的侧枝敏感性网络来解决这一差距。通过包括适应性实验室进化、药敏测试、适合性评估和详细的生物信息学分析在内的综合方法，潜在的结果包括识别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，特别是碳青霉烯类耐药、产超广谱β-内酰胺酶的肠杆菌科细菌。对进化轨迹的更全面的了解将为制定对抗AMR的战略提供信息，并通过允许临床医生使用成熟的抗生素疗法来改善患者的预后，从而将耐药性的出现降至最低。

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.