The role of RNA repair in bacterial responses to translation-inhibiting antibiotics

RNA修复在细菌对翻译抑制抗生素的反应中的作用

• 批准号: BB/Y004035/1
• 负责人: Andrea Weisse
• 金额: $ 33.85万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY004035%2F1
• 关键词: role; RNA; repair; bacterial; responses

Antibiotic resistance happens when bacteria become resistant to the drugs that were designed to kill them. This means that the drugs become less effective at treating infections. It can lead to the development of superbugs that are very difficult and sometimes impossible to treat, leading to longer illness, higher healthcare costs, and in severe cases, death. Antibiotic resistance is considered a major global health threat that already causes disruption to health services and leads to many deaths every year. Unless we find ways to limit the development and spread of resistance, it is set to become worse, and with many treatments and surgeries relying on antibiotics to prevent infections, resistance has the potential to uproot modern medicine as we know it.Resistance can evolve naturally over time, but this is often accelerated by the overuse or misuse of antibiotics. Antibiotic tolerance is a major bottleneck in designing responsible treatment strategies that optimise the use of antibiotics. Tolerance is when bacteria can survive exposure to antibiotics that would normally kill them. This happens before resistance develops and typically requires higher doses of antibiotics or longer treatment. We propose to study a type of tolerance that allows bacteria to keep growing when exposed to antibiotics that target the ribosome, which is the core molecular machinery that produces proteins needed for cellular function and growth. Recent research has shown that when bacteria are exposed to these drugs, some of the cells activate a specific molecular repair system, the Rtc system, and that these cells can keep growing despite the antibiotics. The Rtc system helps cells repair damaged RNA, which performs many vital functions in cells and makes up a sizeable part of the ribosome itself. We seek to understand how RNA repair by Rtc helps bacteria survive antibiotics. We will study how Rtc interacts with ribosomes and how this affects the growth of individual bacterial cells. We will use data to create a computer model that describes the detrimental actions of antibiotics to ribosomes and the counter repair actions of Rtc. Computer simulations are much faster than real-world experiments, and so can help us speed up the development of new scientific insights and solutions, which typically require lengthy rounds of trial-and-error experiments. The computational model will be able to predict how bacteria will respond to antibiotics, and it will help us understand why some bacteria are more tolerant than others and how they can switch between tolerant and susceptible states. We will use the model to help us produce new hypotheses on how to develop better treatments for infections, which will guide future experimental work and shed light on how to slow down the development of resistance.

当细菌对旨在杀死它们的药物产生耐药性时，就会发生抗生素耐药性。这意味着这些药物在治疗感染方面的效果变差。它可能导致超级细菌的发展，这些超级细菌非常难以治疗，有时甚至不可能治疗，导致更长的疾病，更高的医疗费用，在严重的情况下，死亡。抗生素耐药性被认为是一个主要的全球健康威胁，已经造成卫生服务中断，每年导致许多人死亡。除非我们找到限制耐药性的发展和传播的方法，否则它将变得更糟，而且许多治疗和手术都依赖抗生素来预防感染，正如我们所知，耐药性有可能将现代医学连根拔起。耐药性可以随着时间的推移自然进化，但这通常会因过度使用或滥用抗生素而加速。抗生素耐受性是设计负责任的治疗策略以优化抗生素使用的主要瓶颈。耐受性是指细菌可以在暴露于通常会杀死它们的抗生素后存活。这种情况发生在耐药性发展之前，通常需要更高剂量的抗生素或更长时间的治疗。我们建议研究一种耐受性，这种耐受性允许细菌在暴露于靶向核糖体的抗生素时保持生长，核糖体是产生细胞功能和生长所需蛋白质的核心分子机制。最近的研究表明，当细菌暴露于这些药物时，一些细胞会激活一种特定的分子修复系统，即Rtc系统，并且这些细胞可以在抗生素的作用下继续生长。Rtc系统帮助细胞修复受损的RNA，RNA在细胞中执行许多重要功能，并构成核糖体本身的相当大的一部分。我们试图了解Rtc的RNA修复如何帮助细菌在抗生素中存活。我们将研究Rtc如何与核糖体相互作用，以及这如何影响单个细菌细胞的生长。我们将使用数据创建一个计算机模型，描述抗生素对核糖体的有害作用和RTC的反修复作用。计算机模拟比现实世界的实验快得多，因此可以帮助我们加快新的科学见解和解决方案的开发，这通常需要长时间的试错实验。计算模型将能够预测细菌对抗生素的反应，它将帮助我们理解为什么有些细菌比其他细菌更耐受，以及它们如何在耐受和易感状态之间切换。我们将使用该模型来帮助我们提出关于如何开发更好的感染治疗方法的新假设，这将指导未来的实验工作，并阐明如何减缓耐药性的发展。