Convergent evolution of Enterobacteriaceae in epidemiological networks with high antimicrobial use

对抗菌剂产生抗药性的致病细菌是一个全球健康问题。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识别早期预警迹象和有针对性地进行公共卫生干预。我们将研究导致细菌产生抗菌素耐药性的潜在进化机制。与仅在实验室进行的其他研究不同，我们的新方法将使用一种独特的、现实世界中细菌种群在抗菌药物使用率较高的社区中传播的情况来实现这一点。我们将重点关注肠道细菌，它会导致腹泻疾病，是最令人担忧的AMR的病原体。我们将研究真实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在AMR发展过程中发生的遗传变化。然后，我们将在实验室分析数百种细菌菌株，寻找可能有助于细菌发展AMR的行为，并将这些行为与我们的基因变化联系起来，开发模型来量化这些特征中的哪些是最重要的。最后，我们将确认这些基因变化通过在抗菌剂存在的情况下进化出有基因变化和没有基因变化的细菌来促进AMR的发展。这项工作将通过识别AMR在一个重要细菌群中出现的遗传变化来增加我们对AMR关键问题的了解。因为我们是在现实世界中发现基因变化，并在数百个不同的细菌菌株上测试我们的假设，我们知道我们的发现将是重要的，可以帮助我们防止AMR的出现，例如，帮助设计新的实验室测试，用于AMR监测。

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.