Efflux mediated multidrug resistance in Staphylococcus aureus

致病细菌金黄色葡萄球菌(金黄色葡萄球菌)的菌株对几乎所有可用的抗葡萄球菌药物都有抗药性，是患者严重感染的罪魁祸首；在一些医院，这种疫情达到了流行的程度。在这些细菌中，已经出现了对所有类别的抗菌剂的抗药性，包括抗生素和防腐剂--医院环境中常用的消毒剂，这主要是由于获得了抗药性决定因素。这些决定因素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。具体地说，这个项目试图通过将结构不同的抗菌剂泵出细胞来增加我们对赋予耐药性的蛋白质的理解。这些蛋白质在生物体生物学中的重要性从绝大多数药物靶标是膜蛋白的事实中可见一斑。识别如此广泛的化合物的蛋白质被称为多药耐药(MDR)蛋白质，并构成令人不安的临床威胁，因为一个细胞获得一个这样的系统可能会同时降低其对多种抗菌剂的敏感性。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产生抗药性的原因。在这个项目中，我们的目标是鉴定QacA MDR蛋白，它参与从葡萄球菌细胞中泵出许多不同的抗微生物化合物。我们将识别与这些化合物结合的QacA MDR蛋白的区域，并研究该蛋白如何驱逐它们以产生耐药性。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传染病和癌症的多药耐药问题的基础知识。

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.