Structural Topology of a Small Multidrug Resistant Efflux Pump

描述（由申请人提供）：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，由于抗菌素耐药生物体，许多疾病现在变得难以治疗。这些传染病包括艾滋病毒、肺结核、脑膜炎、葡萄球菌感染、流感、淋病、念珠菌和疟疾。目前，5-10%的住院患者发生感染，导致170万例感染，99,000例患者死亡，每年约50亿美元的医疗保健费用（http://www.cdc.gov/ncidod/dhqp/ar.html）。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。在明显找到治疗这些疾病的方法后，细菌已经进化到抵抗治疗（抗生素）。事实上，造成医院感染的细菌中有70%对通常用于治疗它们的抗生素具有耐药性。小的多药耐药（SMR）蛋白家族的成员赋予对几种季铵化合物和其他亲脂性阳离子的抗性，这些阳离子通常用于医院房间的喷雾程序，以减少空气传播和表面细菌的数量。继续过度使用这类抗生素和防腐剂将导致其他菌株进化得更快，以抵抗用于治疗疾病和感染的常用药物。这项研究的长期目标是获得对原核和真核细胞的多样性和复杂性如何进化的分子理解，以便在药物的损害中生存。首先，我将重点关注通过SMR家族中的整体膜蛋白EmrE介导的机制。虽然目前在这个转运蛋白家族中有超过250个成员被确定，但EmrE是了解几个转运蛋白家族中离子耦合机制的原型。在分子分辨率上阐明天然膜环境中的耐药机制是设计新的和更有效的治疗方法来根除致病生物的关键。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药耐药性有一个基本的了解。该项目的长期目标是预测突变菌株的药物结合可能如何改变，以便在发生多药耐药时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.