The roles of a universally conserved DNA-and RNA-binding domain in controlling MRSA virulence and antibiotic resistance

普遍保守的 DNA 和 RNA 结合域在控制 MRSA 毒力和抗生素耐药性中的作用

• 批准号: MR/Y013131/1
• 负责人: Sander Granneman
• 金额: $ 244.4万
• 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=MR%2FY013131%2F1
• 关键词: roles; universally; conserved; DNA; RNA

Antimicrobial medicines have saved millions of lives since the introduction of penicillin in the 1940s. However, their overuse has resulted in the appearance of multidrug-resistant bacteria at a rate that has outpaced the discovery of new antibiotics. The rapid spread of highly virulent and multi-drug-resistant S. aureus strains (such as methicillin-resistant S. aureus (MRSA)) is causing major healthcare problems worldwide as S. aureus skin and respiratory infections can be life-threatening and are becoming increasingly more challenging to treat. MRSA uses several clever tactics to increase its resistance to host immune systems and antibiotic therapies. These include attaching to and killing host cells to extract essential nutrients while evading intracellular immune response and forming biofilm structures that protect the bacterial cells from host immune response and antibiotics. To accomplish this, MRSA must quickly produce new proteins to execute these tasks. Like all organisms, MRSA makes temporary copies of its genes, called messenger RNA (mRNA) molecules. This requires the activity of the transcription machinery, the RNA Polymerase, and other proteins, called transcription factors, that help determine for which genes mRNA copies are generated. The mRNAs can subsequently be read (translated) by another important machinery, called the ribosome, to create proteins. Besides transcription factors, RNA-binding proteins (RBPs) also play vital roles in helping MRSA survive the hostile host environment. By binding to mRNAs, RBPs control how efficiently ribosomes translate the temporary mRNA copies. RBPs can also aid in removing mRNAs that are no longer needed. Although the importance of RBPs for bacteria is well established, we know remarkably little about how these proteins contribute to S. aureus survival during host infection. To address this, we performed pioneering experiments that uncovered many new RBPs in S. aureus. To our surprise, this dataset contained many proteins belonging to a group of transcription factors called Helix-Turn-Helix proteins (HTH). Interestingly, several of these HTH proteins have well-established functions in antibiotic resistance and host immune evasion. Using methodologies from various scientific disciplines, this research programme aims to determine how HTH proteins can recognise distinct DNA and RNA molecules and how important this newly discovered RNA-binding function is for MRSA survival in the host. Finally, using innovative drug discovery techniques, we aim to identify small molecules that control the activity of a select number of HTH proteins. A longer-term goal is to determine whether these small molecules can be repurposed for battling bacterial infections and whether the RNA-binding activities of HTH proteins can be exploited for developing new therapeutics.

自20世纪40年代青霉素问世以来，抗菌药物拯救了数百万人的生命。然而，它们的过度使用导致了多重耐药细菌的出现，其速度超过了新抗生素的发现。高毒力和多药耐药金黄色葡萄球菌菌株(如耐甲氧西林金黄色葡萄球菌(MRSA))的快速传播正在造成全球范围内的重大医疗问题，因为金黄色葡萄球菌皮肤和呼吸道感染可能危及生命，治疗起来越来越困难。MRSA使用几种聪明的策略来增加对宿主免疫系统和抗生素疗法的抵抗力。这些包括附着和杀死宿主细胞以提取必要的营养物质，同时逃避细胞内的免疫反应，并形成生物膜结构，以保护细菌细胞免受宿主免疫反应和抗生素的影响。要做到这一点，MRSA必须迅速产生新的蛋白质来执行这些任务。像所有生物体一样，MRSA会对其基因进行临时复制，称为信使RNA(MRNA)分子。这需要转录机制、RNA聚合酶和其他被称为转录因子的蛋白质的活性，这些蛋白质有助于确定哪些基因产生了mRNA拷贝。随后，被称为核糖体的另一种重要机制可以读取(翻译)mRNAs，以产生蛋白质。除了转录因子，RNA结合蛋白(RBPs)在帮助MRSA在恶劣的宿主环境中生存也起着至关重要的作用。通过与mRNAs结合，限制性商业惯例控制核糖体翻译临时mrna拷贝的效率。限制性商业惯例还有助于去除不再需要的mRNAs。虽然限制性商业惯例对细菌的重要性已经得到证实，但我们对这些蛋白如何在宿主感染期间对金黄色葡萄球菌的生存做出贡献知之甚少。为了解决这个问题，我们进行了开创性的实验，在金黄色葡萄球菌中发现了许多新的限制性商业惯例。令我们惊讶的是，这个数据集包含了许多属于一组转录因子的蛋白质，这些转录因子被称为螺旋-转弯-螺旋蛋白(HTH)。有趣的是，这些HTH蛋白中有几个在抗生素耐药性和宿主免疫逃避方面具有公认的功能。使用来自不同科学学科的方法，这项研究计划旨在确定HTH蛋白如何识别不同的DNA和RNA分子，以及这种新发现的RNA结合功能对MRSA在宿主中的生存有多重要。最后，使用创新的药物发现技术，我们的目标是识别控制选定数量的HTH蛋白活性的小分子。一个更长期的目标是确定这些小分子是否可以被重新用于对抗细菌感染，以及HTH蛋白的RNA结合活性是否可以被开发出新的治疗方法。