Convergent evolution of Enterobacteriaceae in epidemiological networks with high antimicrobial use

对抗菌素具有耐药性的致病细菌是一个全球性的健康问题。虽然有许多研究项目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信号并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。与其他仅在实验室进行的研究不同，我们的新方法将使用独特的、真实的细菌种群在高抗菌素使用群体中传播的情况来实现这一目标。我们将重点关注引起腹泻病的肠道细菌，它们是抗生素耐药性最令人担忧的病原体。我们将研究来自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识别随着AMR发展而发生的遗传变化。然后，我们将在实验室中分析数百种细菌菌株，观察可能有助于细菌产生AMR的行为，并将这些行为与我们的遗传变化联系起来，开发模型来量化哪些特征是最重要的。最后，我们将证实这些遗传变化通过在抗菌素存在的情况下进化有或没有遗传变化的细菌来促进抗菌素耐药性的发展。这项工作将通过确定一个重要细菌群中AMR出现的遗传变化，增加我们对AMR关键问题的认识。因为我们在现实环境中发现了基因变化，并在数百种不同的细菌菌株中测试了我们的假设，我们知道我们的发现将是重要的，可以帮助我们预防抗菌素耐药性的出现，例如，帮助设计用于抗菌素耐药性监测的新的实验室测试。

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.