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: 8208161
• 负责人: Nathaniel J. Traaseth
• 金额: $ 10.8万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208161
• 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（由申请人提供）：多药耐药性是治疗传染病的严重问题。过敏和传染病研究所表明，由于抗菌抗菌的生物，许多疾病现在变得难以治疗。其中一些传染病包括HIV，结核病，脑膜炎，葡萄球菌感染，流感，淋病，念珠菌和疟疾。目前，医院患者中有5-10％的患者感染，导致170万感染，99,000例患者死亡和约50亿美元的年医疗保健费用（http://www.cdc.gov/ncidod/dhqp/ar.ar.html）。仅在15年前，只有12,000人死于类似的感染，这表明该问题显着升高。在发现其中一些疾病的治疗方法之后，细菌已进化为抗药性（抗生素）。实际上，> 70％引起医院感染的细菌对治疗它们的抗生素具有抗药性。小型多药耐药性（SMR）蛋白质家族会议的耐药性对几种Quaternary铵化合物和其他亲脂性阳离子的耐药性，这些阳离子通常用于用于减少空中和表面细菌数量的喷雾烧伤程序中。继续过度使用这种抗生素和防腐剂将导致其他细菌菌株的进化更快，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对原核生物和真核细胞的多样性和复杂性的发展有分子了解，以便在药物的侮辱中生存。首先，我将重点关注SMR家族中一种整体膜蛋白EMRE介导的机制。尽管现在在该家族中确定了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。在天然膜环境中阐明分子分辨率的耐药机制是设计新的，更有效的疗法以消除致病生物的关键。这项研究的影响将是对如何在分子水平上赋予多药耐药的基本了解。该项目的长期目标是预测细菌突变菌株中的药物结合如何改变，以设计新的，更好的抗生素在多药耐药性的情况下。

项目成果

Ligand-induced conformational changes of the multidrug resistance transporter EmrE probed by oriented solid-state NMR spectroscopy.

• DOI: 10.1002/anie.201303091
• 发表时间: 2013-09-23
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Gayen, Anindita;Banigan, James R.;Traaseth, Nathaniel J.
• 通讯作者: Traaseth, Nathaniel J.

Combination of ¹⁵N reverse labeling and afterglow spectroscopy for assigning membrane protein spectra by magic-angle-spinning solid-state NMR: application to the multidrug resistance protein EmrE.

• DOI: 10.1007/s10858-013-9724-z
• 发表时间: 2013-04
• 期刊: Journal of biomolecular NMR
• 影响因子: 2.7
• 作者: Banigan JR;Gayen A;Traaseth NJ
• 通讯作者: Traaseth NJ