Convergent evolution of Enterobacteriaceae in epidemiological networks with high antimicrobial use

高抗菌药物使用流行病学网络中肠杆菌科的趋同进化

• 批准号: BB/V009184/2
• 负责人: Kate Baker
• 金额: $ 26.72万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV009184%2F2
• 关键词: Convergent; evolution; Enterobacteriaceae; epidemiological; networks

Disease-causing bacteria that are resistant to antimicrobials are a global health concern. While there are many research programs looking into the nature and spread of antimicrobial resistance (AMR), little is known about the evolutionary 'stepping stones' that precede the emergence of resistance. Understanding these could help with identifying early warning signs and targeting public health interventions. We will investigate the underlying evolutionary mechanisms that give rise to antimicrobial resistance in bacteria. Unlike other studies, that are done solely in the laboratory, our novel approach will do this using a unique, real-world situation of bacterial populations transmitting among a high antimicrobial use community. We will focus on enteric bacteria, which cause diarrhoeal disease and are pathogens with the most worrying AMR. We will study bacterial genome sequences from real infections and identify genetic changes that happen alongside the development of AMR using the latest bioinformatic methods. We will then analyse hundreds of bacterial strains in the laboratory looking at behaviours that might help the bacteria develop AMR and associate these behaviours with our genetic changes, developing models to quantify which of these signatures is most important. Finally, we will confirm that these genetic changes contribute to the development of AMR by evolving bacteria with and without the genetic change in the presence of antimicrobials. This work will increase our knowledge of the critical problem of AMR by identifying genetic changes underlying the emergence of AMR in an important bacterial group. Because we are finding the genetic changes in a real-world setting and testing our hypotheses across hundreds of different bacterial strains, we know our findings will be important and could help us prevent AMR emergence by, for example, helping design new laboratory testing for use in AMR surveillance.

对抗菌剂具有耐药性的致病细菌是全球健康问题。虽然有许多研究项目正在研究抗菌素耐药性（AMR）的性质和传播，但人们对耐药性出现之前的进化“垫脚石”知之甚少。了解这些可能有助于确定早期预警信号和有针对性的公共卫生干预措施。我们将研究引起细菌抗菌素耐药性的潜在进化机制。与其他仅在实验室中进行的研究不同，我们的新方法将使用在高抗菌剂使用社区中传播的细菌种群的独特的真实情况来实现这一点。我们将重点关注肠道细菌，它们会导致肠道疾病，也是最令人担忧的AMR病原体。我们将研究来自真实的感染的细菌基因组序列，并使用最新的生物信息学方法确定AMR发展过程中发生的遗传变化。然后，我们将在实验室中分析数百种细菌菌株，研究可能有助于细菌发展AMR的行为，并将这些行为与我们的遗传变化联系起来，开发模型来量化这些特征中哪一个最重要。最后，我们将通过在抗菌剂存在下进化具有和不具有遗传变化的细菌来证实这些遗传变化有助于AMR的发展。这项工作将通过确定一个重要细菌群体中AMR出现的遗传变化来增加我们对AMR关键问题的认识。因为我们正在现实世界中发现遗传变化，并在数百种不同的细菌菌株中测试我们的假设，我们知道我们的发现将是重要的，可以帮助我们预防AMR的出现，例如，帮助设计用于AMR监测的新实验室测试。