Multidrug resistance regulatory protein QacR from Staphylococcus aureus

耐药性最重要的机制之一是抗生素和其他化疗药物从细胞中输出。药物输出系统是一个重要的医学问题，因为它们经常出现在导致人类疾病的细菌和寄生虫以及人类癌细胞中。识别并从细胞中输出多种药物的蛋白质被称为多药外排泵。这些多药物外排系统对患者护理和成功治疗构成严重威胁，因为同时产生单一蛋白质的能力使细胞或生物体对几种不同的药物具有抗性。细菌病原体金黄色葡萄球菌（Staphylococcus aureus）或金黄色葡萄球菌（Golden Staph）的菌株（其在全世界的医院中是地方性的）包含这样的多药物输出器的实例，QacA多药物外排泵。QacA出口至少30种不同的抗菌化合物，包括防腐剂和消毒剂。这种蛋白质的产生受传感器蛋白QacR的调节，该传感器蛋白QacR检测许多这些抗微生物化合物的存在。为了了解QacR传感器蛋白如何识别如此广泛的化合物，我们将鉴定并在结构上鉴定结合这些化合物的QacR多药调节蛋白的区域。此外，我们将研究QacR调节QacA泵蛋白生产的方法。该项目将提供基础知识，不仅有助于理解多药耐药的重要过程，而且还将使更有效的抗菌化合物的合理设计，无论是阻止或逃避这些多药外排系统。

One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease, and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful therapy, since the ability to produce a single protein simultaneously renders the cell or organism resistant to several different drugs. Strains of the bacterial pathogen Staphylococcus aureus or Golden Staph, which are endemic in hospitals world-wide, contain an example of such a multidrug exporter, the QacA multidrug efflux pump. QacA exports at least 30 different antimicrobial compounds, including antiseptics and disinfectants. Production of this protein is regulated by a sensor protein, QacR, which detects the presence of a number of these antimicrobial compounds. To understand how the QacR sensor protein can recognise such a wide variety of compounds, we will identify and structurally characterise the regions of the QacR multidrug regulatory protein which bind these compounds. Additionally, we will examine the means by which QacR regulates the production of the QacA pump protein. This project will provide fundamental knowledge that will not only help with understanding the important process of multidrug resistance but will also enable the rational design of more effective antibacterial compounds that either block or evade these multidrug efflux systems.