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

自20世纪40年代引入青霉素以来，抗微生物药物挽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速度。高毒力和多重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））的迅速传播正在全球范围内引起重大卫生保健问题，因为金黄色葡萄球菌皮肤和呼吸道感染可能危及生命，并且治疗变得越来越具有挑战性。耐甲氧西林金黄色葡萄球菌使用几种巧妙的策略来增强其对宿主免疫系统和抗生素治疗的抵抗力。这些包括附着和杀死宿主细胞以提取必需的营养物质，同时逃避细胞内免疫反应，形成生物膜结构，保护细菌细胞免受宿主免疫反应和抗生素的侵害。为了做到这一点，MRSA必须迅速产生新的蛋白质来执行这些任务。像所有的生物体一样，MRSA会对其基因进行临时复制，称为信使RNA （mRNA）分子。这需要转录机制的活动，RNA聚合酶和其他蛋白质，称为转录因子，帮助确定哪些基因的mRNA副本生成。mrna随后会被另一种重要的机器——核糖体——读取（翻译），从而产生蛋白质。除了转录因子外，rna结合蛋白（rbp）在帮助MRSA在敌对宿主环境中生存方面也起着至关重要的作用。通过与mRNA结合，rbp控制核糖体翻译临时mRNA拷贝的效率。rbp还可以帮助去除不再需要的mrna。虽然rbp对细菌的重要性已经得到证实，但我们对这些蛋白在宿主感染期间如何促进金黄色葡萄球菌存活知之甚少。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rbp。令我们惊讶的是，这个数据集包含了许多属于一组被称为Helix-Turn-Helix蛋白（HTH）的转录因子的蛋白质。有趣的是，这些HTH蛋白中的一些在抗生素耐药性和宿主免疫逃避中具有公认的功能。利用不同科学学科的方法，本研究计划旨在确定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在宿主中的存活有多重要。最后，利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。一个长期的目标是确定这些小分子是否可以重新用于对抗细菌感染，以及HTH蛋白的rna结合活性是否可以用于开发新的治疗方法。

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.