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

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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.