Structural Topology of a Small Multidrug Resistant Efflux Pump

小型多药耐药外排泵的结构拓扑

• 批准号: 7893390
• 负责人: Nathaniel J. Traaseth
• 金额: $ 15.88万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893390
• 关键词: Adopted; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Binding; Binding Sites; Biochemical; Biological; Candida; Cations; Cell Wall Alteration; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Charge; Communicable Diseases; Coupled; Cryoelectron Microscopy; Data; Disease; Drug Efflux; Drug Transport; Drug resistance; Drug usage; Environment; Escherichia coli; Ethidium; Eukaryotic Cell; Event; Family; Fluorescence; Fogs; Goals; Gonorrhea; HIV; Health Care Costs; Homidium Bromide; Hospitals; Hypersensitivity; Image; In Vitro; Infection; Influenza; Institutes; Integral Membrane Protein; Ions; Lead; Length; Ligands; Link; Lipid Bilayers; Local Anti-Infective Agents; Malaria; Mediating; Membrane; Membrane Proteins; Meningeal Tuberculosis; Methods; Microbial Drug Resistance; Mind; Modeling; Molecular; Molecular Conformation; Monitor; Multi-Drug Resistance; Mutate; Mutation; Nosocomial Infections; Organism; P-Glycoproteins; Patients; Pharmaceutical Preparations; Play; Preparation; Procedures; Prokaryotic Cells; Protein Binding; Protein Family; Protein S; Proteins; Protons; Public Health; Research; Resistance; Resolution; Risk; Role; Sampling; Shapes; Staphylococcal Infections; Staphylococcus aureus; Structure; Surface; Testing; antibiotic efflux; antimicrobial; base; design; dimer; effective therapy; efflux pump; infectious disease treatment; killings; member; prototype; quaternary ammonium compound; reconstitution; research study; resistance mechanism; scaffold; solid state nuclear magnetic resonance; therapy design

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.

描述（申请人提供）：多药耐药性是感染性疾病治疗中的一个严重问题。过敏症和传染病研究所指出，由于抗生素耐药生物体，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%的医院患者发生感染，导致170万例感染，99，000例患者死亡和每年约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12，000人死于类似的感染，这表明这个问题的严重性。在显然找到这些疾病的治疗方法后，细菌已经进化到抵抗治疗（抗生素）。事实上，超过70%的引起医院感染的细菌对通常用于治疗它们的抗生素具有耐药性。小多药耐药（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，这些化合物和其他亲脂性阳离子通常用于医院病房的喷雾雾化程序，以减少空气传播和表面细菌的数量。继续过度使用这些抗生素和防腐剂将导致其他细菌菌株进化得更快，以抵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水平上了解原核和真核细胞的多样性和复杂性是如何进化的，以便在药物的侵害下生存下来。作为一个开始，我将集中在通过EmrE，SMR家族内的一个完整的膜蛋白介导的机制。虽然现在有超过250个成员在这个家庭中确定，EmrE是了解几个转运蛋白家族内的离子耦合机制的原型。在天然膜环境中以分子分辨率阐明耐药机制是设计新的和更有效的疗法以根除病原生物体的关键。这项研究的影响将有助于在分子水平上对病原体如何产生多药耐药性的基本理解。该项目的长期目标是预测突变菌株中药物结合如何改变，以便在发生多药耐药性时设计新的更好的抗生素。