Dissecting the bacterial genetics of bloodstream infection

剖析血流感染的细菌遗传学

• 批准号: MR/X007197/1
• 负责人: James Connolly
• 金额: $ 175.13万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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=MR%2FX007197%2F1
• 关键词: Dissecting; bacterial; genetics; bloodstream; infection

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.

大肠杆菌是最常与血流感染相关的细菌病原体。这是一个主要的健康问题，考虑到患者获得这样的感染可能发展败血症，身体的潜在致命的连锁反应，感染的血流。脓毒症每年影响全球约5000万人，死亡率高达五分之一。此外，血液感染是2019年由抗菌素耐药性直接导致的127万例死亡中的三分之一。世界卫生组织将E.大肠杆菌作为发现新治疗策略的关键优先事项，因为它是导致耐药性引起死亡的主要生物体。目前有大约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。大肠杆菌，不可避免的是，它们不会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，如果没有发现新的治疗方法，到2050年，每年死于抗菌素耐药性感染的人数估计将增加到1000万。解决这个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如何引起感染。细菌基因就像蓝图一样，描述了它们赖以生存的分子机制。然而，病原体可以以独特的方式改变它们所需的基因，这使得它们的蓝图难以根据感染类型而理解。目前，我们还不清楚E。大肠杆菌利用其分子机制感染血液并扩散到全身。我将通过发现大肠杆菌所需的特定基因和相关的分子过程来解决这个问题。大肠杆菌导致潜在致命的血液感染。通过了解病原体在宿主体内发挥作用的分子要求，我们可以利用这一知识开发疫苗或抑制剂，专门阻断这些过程。这项研究将揭示血流感染的潜在过程，因此有可能揭示未来药物开发迫切需要的靶点。