Ecological and Evolutionary Drivers of Antibiotic Resistance in Patients

患者抗生素耐药性的生态和进化驱动因素

• 批准号: EP/Y031067/1
• 负责人: Craig MacLean
• 金额: $ 269.79万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY031067%2F1
• 关键词: Ecological; Evolutionary; Drivers; Antibiotic; Resistance

Antibiotic resistance in pathogenic bacteria poses a fundamental threat to human health. The overarching aim of this project is todetermine the ecological and evolutionary processes that drive the emergence and loss of antibiotic resistance in hospitalizedpatients. The first objective of this project is to uncover drivers of resistant infections. Specifically, we will determine the relativecontribution of (i) de novo variation, (ii) pre-existing variation and (iii) superinfection to the emergence of resistance as a function ofantibiotic treatment. The second objective of the project is to determine key factors that shape the stability of resistance in patients.Specifically, we will (i) measure the cost of resistance, (ii) test for compensatory evolution in resistant populations and (iii) test the hypothesis that high fitness costs accelerate the loss of antibiotic resistance in the absence of antibiotic treatment. The third objective of this project is to determine the impact of antibiotic treatment on genome evolution. Specifically, we will (i) measure the impact of antibiotic treatment on the rate of molecular evolution and (ii) systematically identify genetic drivers of resistance. To achieve these objectives we will use samples and data collected during ASPIRE-ICU, a large scale clinical trial of infections caused by the opportunistic pathogen P.aeruginosa. Characterization of isolates from large numbers of longitudinally sampled patients with varying antibiotic treatment regimes will allow us to study the phenotypic and genomic responses to antibiotic treatment. Experimental evolution with clinical isolates will let us directly test the role of key variables that are predicted to shape antibiotic resistance. The novel combination of clinical sampling, experimental evolution and genomic analyses will allow us to generate unprecedented insights intIn this project we will investigate the ecological and evolutionary drivers of antibiotic resistant infection.

致病细菌中的抗生素耐药性对人类健康构成了根本威胁。该项目的总体目的是确定生态和进化过程，这些过程推动了住院病患者中抗生素耐药性的出现和丧失。该项目的第一个目的是发现抗性感染的驱动因素。具体而言，我们将确定（i）从头变化，（ii）先前存在的变化和（iii）抗抗性作为抗生素治疗的函数的重新差异。该项目的第二个目标是确定塑造患者抗药性稳定性的关键因素。特别是，（i）测量抵抗力的成本，（ii）测试抗性种群的补偿性进化，以及（iii）检验假说，高素质成本在缺乏抗生素治疗的情况下会加速抗生素耐药性的丧失。该项目的第三个目标是确定抗生素治疗对基因组进化的影响。具体而言，我们将（i）衡量抗生素处理对分子进化速率的影响，并系统地识别耐药性遗传驱动因素。为了实现这些目标，我们将使用Aspire-ICU期间收集的样品和数据，这是一项由机会性病原体P.Aeruginosa引起的大规模临床试验。来自大量纵向抽样抗生素治疗方案的分离株的表征将使我们能够研究对抗生素治疗的表型和基因组反应。临床分离株的实验进化将使我们直接测试预测塑造抗生素耐药性的关键变量的作用。临床抽样，实验进化和基因组分析的新型组合将使我们能够产生前所未有的见解信息，我们将研究抗生素耐药性感染的生态和进化驱动因素。