Structural Topology of a Small Multidrug Resistant Efflux Pump

描述(申请人提供)：多药耐药是传染病治疗中的一个严重问题。过敏和传染病研究所指出，由于抗菌素耐药性的微生物，许多疾病现在变得难以治疗。其中一些传染病包括艾滋病毒、结核病、脑膜炎、葡萄球菌感染、流感、淋病、念珠菌和疟疾。目前，5%-10%的住院患者会发生感染，导致170万人感染，99,000人死亡，每年的医疗费用(http://www.cdc.gov/ncidod/dhqp/ar.html).)约为50亿美元就在15年前，只有1.2万人死于类似的感染，这表明这个问题的严重程度。在显然找到了治疗其中一些疾病的方法后，这种细菌进化成了对治疗(抗生素)的抵抗力。事实上，引起医院感染的细菌中有70%对治疗它们的常用抗生素具有抗药性。小分子多药耐药(SMR)蛋白家族的成员对几种季铵化合物和其他亲脂性阳离子具有抵抗力，这些阳离子通常用于医院房间的喷雾程序，以减少空气和表面细菌的数量。继续过度使用这种抗生素和防腐剂将导致其他细菌菌株进化得更快，以对抗用于治疗疾病和感染的常见药物。这项研究的长期目标是从分子上了解原核和真核细胞的多样性和复杂性是如何进化的，以便在药物的侮辱下生存下来。首先，我将重点介绍通过EmRE介导的机制，EmRE是SMR家族中的一种完整的膜蛋白。虽然现在在这个家族中发现了超过250个成员，但EmRE是理解几个转运蛋白家族中离子耦合机制的原型。在天然膜环境中从分子水平上阐明耐药机制是设计新的、更有效的治疗方法以根除病原体的关键。这项研究的影响将有助于在分子水平上对致病生物如何产生多重耐药做出基本的理解。该项目的长期目标是预测突变菌株中的药物结合可能会如何改变，以便在出现多重耐药的情况下设计出新的更好的抗生素。

DESCRIPTION (provided by applicant): Multidrug resistance is a serious problem in the treatment of infectious diseases. The Institute of Allergy and Infectious Diseases indicates that many diseases are now becoming difficult to treat due to antimicrobial-resistant organisms. Some of these infectious diseases include HIV, tuberculosis, meningitis, staphylococcal infection, influenza, gonorrhea, Candida, and malaria. Currently 5-10% of hospital patients develop an infection, leading to 1.7 million infections, 99,000 patient deaths and ~$5 billion in annual healthcare costs (http://www.cdc.gov/ncidod/dhqp/ar.html). Just 15 years ago, only 12,000 people died from similar infections, indicating a significant elevation of the problem. After apparently finding cures for some of these diseases, the bacteria have evolved to resist treatments (antibiotics). In fact, > 70% of bacteria causing hospital infections are resistant to antibiotics commonly used to treat them. Members of the small multidrug resistance (SMR) protein family confer resistance to several quaternary ammonium compounds and other lipophilic cations that are commonly used in spray-fogging procedures for hospital rooms to reduce the number of airborne and surface bacteria. Continued overuse of such antibiotics and antiseptics will lead to other bacterial strains evolving even faster to resist common drugs used to treat disease and infection. The long-term goal of this research is to gain a molecular understanding of how diversity and complexity in both prokaryotic and eukaryotic cells have evolved in order to survive the insults of drugs. As a start, I will focus on the mechanism mediated through EmrE, an integral membrane protein within the SMR family. Although there are now greater than 250 members identified within this family, EmrE is the prototype for understanding the ion-coupled mechanism within several transporter families. Elucidating the resistance mechanism at molecular resolution in the native membrane environment is key to the design of new and more effective therapies to eradicate pathogenic organisms. The impact of this research will be to contribute a basic understanding toward how multidrug resistance is conferred to pathogenic organisms on a molecular level. The long-term goal of this project is to predict how drug binding might be altered in mutated strains of bacteria, so as to design new and better antibiotics in the event of multidrug resistance.