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

识别临床环境中可利用的稳健的附带敏感性表型，以最大限度地减少抗生素耐药性的出现

• 批准号: 2757457
• 金额: --
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2757457
• 关键词: Identifying; Robust; Collateral; Sensitivity; Phenotypes

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.

T1基础研究-T2临床研究抗药性（AMR）对全球健康构成了重大威胁。迫切需要限制AMR出现的新策略。一种有前途的方法涉及对进化生物学的开发，特别是一种称为侧支敏感性的现象，由于突变导致对不相关的抗生素的抗性，因此可能会发生对一种抗生素的敏感性的变化。通过利用顺序抗生素治疗选择抗性，可以利用与抗生素耐药性突变相关的权衡。为了使高敏表型可以转移到临床环境中，必须在各种细菌菌株和遗传背景上建立其可重复性和保护性。但是，现有的研究主要集中在单个生长条件下具有多种抗生素的单菌株的发展，从而使知识差距有关不同菌株和条件的侧支灵敏度网络的稳健性。该项目的目的是通过识别1）实验室培养基来解决这一差距，从而导致细菌沿着体内观察到的相同进化途径的耐药性演变，而2）2）在不同菌株和基因组背景中可重复可重复的强大侧支敏感性网络。通过全面的方法，包括适应性实验室进化，易感性测试，健身评估和详细的生物信息学分析，潜在的结果包括鉴定抗生素对，可以依次且可以互换，以提高对其他抗生素的细菌敏感性，并针对其他抗生素敏感 - 抗性，产生ESBL的肠杆菌科。通过允许临床医生使用经过验证的抗生素疗法来最大程度地减少抵抗力的出现，对进化轨迹的更全面了解将为打击AMR和改善患者的策略的制定提供信息。