Dissecting the bacterial genetics of bloodstream infection

大肠杆菌是最常与血液感染相关的细菌病原体。这是一个主要的健康问题，因为感染这种病毒的病人可能会患上败血症，这是人体对血液感染的潜在致命连锁反应。败血症每年影响全球约5000万人，死亡率高达五分之一。此外，在2019年由抗菌素耐药性直接导致的127万人死亡中，血液感染占三分之一。世界卫生组织将大肠杆菌列为发现新治疗策略的关键优先事项，因为它是导致耐药性死亡的主要微生物。目前大约有40种新的抗生素正在开发中。然而，其中许多对革兰氏阴性菌（如大肠杆菌）没有活性，并且不可避免地不能全部获得临床使用的批准。因此，很明显，这些潜在的药物将无法满足社会日益增长的需求，如果不发现新的治疗方法，估计到2050年，每年因抗微生物药物耐药性感染而死亡的人数将上升到1 000万人。解决这一问题的一个策略是设计针对病原体的靶向治疗。然而，为了确定这些目标是什么，我们必须首先深入了解细菌是如何引起感染的。细菌基因就像描绘它们赖以生存的分子机制的蓝图。然而，病原体可以以独特的方式改变它们需要的基因，这使得它们的蓝图很难根据感染的类型来理解。我们目前还不清楚大肠杆菌是如何利用其分子机制感染血液并扩散到全身的。我将通过发现大肠杆菌引起潜在致命血液感染所需的特定基因和相关分子过程来解决这一空白。通过了解病原体在宿主内发挥作用的分子要求，我们可以利用这些知识开发特异性阻断这些过程的疫苗或抑制剂。这项研究将揭示血液感染的潜在过程，因此有可能揭示未来药物开发迫切需要的靶点。

Escherichia coli is the bacterial pathogen most often associated with bloodstream infection. This is a major health concern considering that a patient acquiring such an infection can develop sepsis, the body's potentially lethal chain reaction to infection of the bloodstream. Sepsis affects around 50 million people worldwide every year, with a frightening one in five chance of death. Furthermore, bloodstream infections were responsible for one third of the 1.27 million deaths directly caused by antimicrobial resistance in 2019. The World Health Organization ranks E. coli as a critical priority for discovery of new treatment strategies, due to it being the leading organism responsible for deaths arising from drug resistance. There are currently around 40 new antibiotics in development. However, many of these are not active against Gram-negative bacteria such as E. coli and it is inevitable that they will not all win approval for clinical use. It is therefore clear that these potential drugs will not meet the increasing demand in society and, without the discovery of new treatment approaches, annual deaths from antimicrobial resistant infections are estimated to rise to 10 million by 2050. One strategy to combat this problem is to design targeted treatments against pathogens. However, in order to identify what these targets are, we must first gain a deep, fundamental understanding of how bacteria cause infection. Bacterial genes act as blueprints describing the molecular machinery that they use to live. However, pathogens can alter which genes they require in unique ways, making their blueprints difficult to understand depending on the type of infection. We currently lack an understanding of how E. coli uses its molecular machinery to infect the bloodstream and spread throughout the body. I will address this gap by discovering the specific genes and associated molecular processes that are required for E. coli to cause potentially lethal bloodstream infections. By understanding the molecular requirements of pathogens to function within the host, we can exploit this knowledge to develop vaccines or inhibitors that specifically block these processes. This research will reveal the underlying processes of bloodstream infection and therefore has the potential to reveal urgently needed targets for future drug development.