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具有抗性时，就会发生抗生素耐药性。这意味着药物在治疗感染方面的有效性降低。它可能导致超级细菌的发展，这些超级细菌非常困难，有时不可能治疗，导致疾病更长，更高的医疗保健成本以及在严重的情况下死亡。抗生素抗性被认为是全球主要的健康威胁，已经导致卫生服务中断，并导致每年许多死亡。除非我们找到限制阻力发展和传播的方法，否则它将变得更糟，并且由于许多治疗和手术依靠抗生素来防止感染，抗药性可能会捕捉我们所知道的现代医学的潜力。抗性随着时间的推移可以自然地发展，但这通常会因抗生素过度使用或滥用抗生素而加速。抗生素耐受性是设计优化抗生素使用的负责任治疗策略的主要瓶颈。耐受性是在细菌可以在通常会杀死它们的抗生素中幸存下来的时候。这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的治疗方法。我们建议研究一种耐受性，该耐受性允许细菌暴露于靶向核糖体的抗生素时继续生长，这是产生细胞功能和生长所需的蛋白质的核心分子机械。最近的研究表明，当细菌暴露于这些药物时，某些细胞会激活特定的分子修复系统，RTC系统，并且尽管有抗生素，这些细胞仍可以继续生长。 RTC系统可帮助细胞修复受损的RNA，该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部分。我们试图了解RTC修复RNA如何帮助细菌在抗生素中生存。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，该模型描述了抗生素对核糖体和RTC的反修复动作的有害作用。计算机仿真比现实世界实验快得多，因此可以帮助我们加快新科学见解和解决方案的发展，这通常需要漫长的反复试验实验。计算模型将能够预测细菌对抗生素的反应，这将有助于我们理解为什么某些细菌比其他细菌更宽容，以及它们如何在耐受性和易感状态之间切换。我们将使用该模型来帮助我们提出有关如何为感染开发更好治疗方法的新假设，这将指导未来的实验工作，并阐明如何减缓抵抗力的发展。