Efflux mediated multidrug resistance in Staphylococcus aureus

致病菌金黄色葡萄球菌（金黄色葡萄球菌）的菌株对几乎所有可用的抗葡萄球菌剂具有抗性，是患者中严重感染的原因;在一些医院，这种爆发达到流行病的程度。在这些细菌中，对所有类别的抗菌剂（包括医院环境中常用的抗生素和防腐剂-消毒剂）都出现了耐药性，这主要是由于获得了耐药性决定因素。这些决定簇编码的蛋白质为细菌细胞提供了一系列不同的生化机制，以逃避抗生素化疗。具体来说，该项目旨在增加我们对蛋白质的理解，这些蛋白质通过将结构不同的抗菌剂泵出细胞来赋予抗性。绝大多数药物靶点是膜蛋白，这一事实暗示了这些蛋白质在生物体生物学中的重要性。识别这种广谱化合物的蛋白质被称为多药耐药（MDR）蛋白，并且呈现令人不安的临床威胁，因为细胞获得一个这样的系统可能同时降低其对许多抗菌剂的敏感性。类似的MDR泵在自然界中广泛存在，并被认为是许多病原体和人类癌细胞对抗生素和其他化疗药物的耐药性。在这个项目中，我们的目标是克隆QacA MDR蛋白，该蛋白参与从葡萄球菌细胞中泵送许多不同的抗菌化合物。我们将确定QacA MDR蛋白结合化合物的区域，并研究蛋白质如何排出它们以产生抗性。这些研究是设计能够绕过这些耐药泵的更有效的抗菌化合物的先决条件，也将提供适用于其他感染性疾病和癌症中MDR问题的基础知识。

Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph), resistant to almost all available anti-staphylococcal agents, are responsible for serious infections among patients; in some hospitals such outbreaks reach epidemic proportions. In these bacteria, resistance has emerged to all classes of antimicrobial agents, including antibiotics and antiseptics-disinfectants commonly used in the hospital environment, largely due to the acquisition of resistance determinants. These determinants encode proteins that provide the bacterial cell with a range of different biochemical mechanisms to evade antibiotic chemotherapy. Specifically, this project seeks to increase our understanding of proteins that confer resistance by pumping structurally-dissimilar antimicrobials out of the cell. The importance of these proteins in the biology of organisms is implied by the fact that an overwhelming majority of the drug targets are membrane proteins. Proteins which recognise such a broad spectrum of compounds are called multidrug resistance (MDR) proteins and present a disturbing clinical threat since the acquisition of one such system by a cell may simultaneously decrease its susceptibility to a number of antimicrobials. Similar MDR pumps are widespread in nature and are credited for resistance to antibiotics and other chemotherapeutic drugs in many pathogenic organisms and in human cancer cells. In this project, we aim to characterise the QacA MDR protein which is involved in pumping many different antimicrobial compounds from staphylococcal cells. We will identify the regions of the QacA MDR protein which bind the compounds and examine how the protein expels them to give resistance. These studies are a prerequisite for the design of more effective antibacterial compounds able to bypass these drug resistance pumps and will also provide fundamental knowledge applicable to the problem of MDR in other infectious diseases and cancer.