The epidemiology of transmissible antimicrobial resistance among Shigella species

抗生素、抗病毒药物和抗真菌药物等抗微生物药物使医学发生了革命性的变化。它们对于抗击疾病是必不可少的，并使手术和癌症治疗更安全。不幸的是，这些药物所对抗的许多微生物正变得“耐药”，抗菌药物不再起作用。在世界范围内，每年有超过70万人死于抗菌素耐药性疾病。抗菌素耐药性(AMR)正在迅速增加；联合国预测，如果不采取行动，到2050年，每年死于抗菌素耐药疾病的人数可能会攀升至1000万人。我们的工作重点是志贺氏菌的AMR。志贺氏菌是低收入和中等收入国家儿童严重腹泻的主要原因，也会在男男性行为者中引起性传播疾病。每年有超过2亿人感染志贺氏菌，超过20万人死亡。目前还没有针对志贺氏菌的广泛可用的疫苗，而且，像许多其他细菌一样，它们对抗菌素产生了抗药性。世界卫生组织将志贺氏菌列为抗菌素耐药性(AMR)优先考虑的十二种生物之一。当细菌繁殖时，它们通常分裂成两个子细胞。AMR基因从亲代细胞传递到子代细胞的过程被很好地理解和监测。然而，许多细菌物种也能够使用移动遗传元件(MGES)在不同细胞之间转移AMR基因。这就是所谓的“可传染的AMR”，顾名思义，它涉及两个细菌之间的基因直接转移。我们的试点工作表明，志贺氏菌中约有一半的AMR是可传播的。我们不完全了解MGES如何在细菌种群中移动，但很明显，一些AMR-MGES留在细菌中，从而导致大量感染，而另一些则不会。要了解AMR MGES如何在细菌种群中传播，以及哪些MGES会成功，是具有挑战性的；我们需要考虑AMR基因、MGE、细菌和人类宿主。志贺氏菌是研究传染性AMR的优秀模型，因为志贺氏菌感染已经被国家公共卫生监测小组跟踪，而且因为它只在人类中引起感染(所以我们不需要考虑不同宿主的影响)。这意味着我们可以使用常规监测数据来了解细菌和人类宿主是如何相互作用的。该项目将首次对人类宿主中最重要的志贺氏菌进行全球概述。它将描述所有携带重要医学上的AMR的MGES的特征，以了解哪些MGES引起的感染最多，以及MGES是如何在细菌种群中移动的。然后，我们将研究MGES的哪些类型和功能是在现实世界中驱动这种可传播的AMR的最重要因素。这将使我们能够了解AMR-MGES的生物学，并确定可能作为新的AMR细菌出现的“早期预警信号”的特征。我们希望我们的研究通过识别新出现的AMR并了解哪些人群最有可能感染志贺氏菌AMR来改善卫生系统。在未来，这将使这些人能够获得专门的医疗保健，如筛查和量身定做的抗菌建议。我们已经建立了一支团队，其中包括专门从事AMR的学术研究人员和负责四个国家的疾病监测的公共卫生专家。这将确保我们的新发现和新方法对公共卫生从业者有用，并将在短期内用于现实世界。虽然这个项目的重点是志贺氏菌，但我们的新方法将被设计成使它们在未来更容易用于其他细菌物种。

Antimicrobial drugs, such as antibiotics, antivirals and antifungals, revolutionised medicine. They are essential for fighting diseases, and make surgery and cancer therapies safer. Unfortunately, many of the microbes which these drugs fight are becoming 'resistant' and the antimicrobial drugs no longer work. Worldwide, more than 700,000 people each year die due to antimicrobial drug-resistant disease. Antimicrobial resistance (AMR) is increasing rapidly; the United Nations predicts that number of deaths due to antimicrobial drug-resistant disease may climb to as many as 10 million deaths per year by 2050 if no action is taken.Our work focuses on AMR in Shigella bacteria. Shigella are the main cause of severe diarrhoea among children in low-and middle-income countries and also cause sexually transmissible illness in men who have sex with men. Over 200 million people become ill from Shigella each year and over 200,000 people die. There is no widely available vaccine against Shigella and, like many other bacteria, they are becoming resistant to antimicrobials. The World Health Organisation list Shigella as one of twelve priority organisms for antimicrobial resistance (AMR). When bacteria reproduce, they typically divide into two daughter cells. The process by which AMR genes are passed from parent to daughter cells is well understood and monitored. However, many bacterial species are also able to transfer genes for AMR between different cells using mobile genetic elements (MGEs). This is called 'transmissible AMR' and - as the name suggests - involves direct transfer of genes between two bacteria. Our pilot work shows that about half of the AMR in Shigella is transmissible. We don't fully understand how MGEs move about in bacterial populations, but it is clear that some AMR-MGEs stay in bacteria which go on to cause lots of infections, while others don't.Understanding how AMR MGEs spread amongst bacterial populations, and which MGEs will be successful is challenging; we need to consider the AMR gene, the MGE, the bacteria, and the human hosts. Shigella is an excellent model to study transmissible AMR because Shigella infections are already tracked by national public health surveillance teams, and because it only causes infections in humans (so we don't need to consider the effects of different hosts). This means that we can use routine surveillance data to understand how the bacteria and the human hosts interact. This project will, for the first time, create a global overview of the most important Shigella bacteria in their human hosts. It will characterise all the MGEs carrying medically important AMR to understand which ones are causing the most infections and how the MGEs are moving through the bacterial populations. We will then study which types, and what features, of MGEs are the most important factors for driving this transmissible AMR in the real-world. This will enable us to understand the biology of AMR-MGEs and identify features that might act as 'early warning signs' for the emergence of new AMR bacteria. We want our research to make health systems better by identifying newly emerging AMR and understanding which groups of people are at most risk from Shigella AMR. In the future this will enable these people to be given specialised healthcare, such as screening and tailored antimicrobial recommendations. We have built a team that includes academic researchers specialising in AMR and public health specialists who are responsible for disease surveillance across four countries. This will ensure that our new findings and new approaches are useful for public health practitioners and that they will be adopted for use in real-world settings in the near term. Although this project focuses on Shigella, our new methods will be designed to make them easy to use for other bacterial species in the future.