Permeability Barriers of Gram-negative Pathogens and Approaches to Bypass Them

革兰氏阴性病原体的渗透性屏障及其绕过方法

• 批准号: 9914090
• 负责人: HELEN I ZGURSKAYA
• 金额: $ 49.86万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-08 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914090
• 关键词: Acinetobacter baumannii; Address; Affect; Affective; Analytical Chemistry; Antibiotic Resistance; Antibiotics; Area; Bacteria; Binding; Biophysics; Burkholderia; Bypass; Cell membrane; Cells; Chemicals; Data; Diffusion; Escherichia coli; Goals; Gram-Negative Bacteria; Growth; Libraries; Logistics; Mathematics; Medical; Membrane; Methods; Modeling; Outcome; Penetration; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiology; Property; Proteins; Pseudomonas aeruginosa; Pump; Research; Research Personnel; Resistance; Role; Source; Structure; Structure-Activity Relationship; Technology; Testing; The Sun; Therapeutic; Vancomycin; Walkers; antibiotic efflux; bacterial resistance; base; cell envelope; clinically significant; design; drug development; drug discovery; efflux pump; experience; hydrophilicity; novel; novel strategies; pathogen; success; tool; uptake; virtual

Permeability barriers of Gram-negative pathogens and approaches to bypass them A major source of resistance in Gram-negative species is the permeability barrier created by a synergistic action of slow uptake and active efflux of antibiotics across the outer membrane. The proposed research will address a critical need to understand penetration across the cell envelope of Gram-negative species and to develop antibiotics affective against these pathogens. In preliminary studies, we established novel mathematical and empirical approaches to analyze drug uptake across a two-membrane barrier with active efflux. Based on these results, we formulated a hypothesis that permeation and hence activities of antibiotics are affected by bacterial barriers and active efflux differently and that these differences are defined by physicochemical properties of antibiotics. To critically test this hypothesis, we will apply the new formalism and methods to analyze permeability barriers of Pseudomonas aeruginosa, Acinetobacter baumannii and Burkholderia spp. that differ significantly in the composition of their outer membranes and efflux pumps. These pathogens are notorious for their virtually unbreachable permeability barriers. Our goal is to establish structure-activity relationships between drug uptake, efflux and inhibitory activities for a select library of compounds in the context of barriers with different permeability properties. The proposed studies will define the limits of barriers and compounds and will create a framework for optimization of antibiotics targeting the “impermeable” pathogens.

革兰氏阴性病原体的渗透性障碍和绕过方法 他们 革兰氏阴性物种中的主要抵抗力是由A产生的渗透性屏障 缓慢摄取和抗生素在外膜上的积极排出的协同作用。这 拟议的研究将解决了解整个细胞渗透的迫切需求 革兰氏阴性物种的包膜，并发展出对这些抗生素的影响 病原体。在初步研究中，我们建立了新颖的数学和经验方法 分析具有主动外排两个膜屏障的药物摄取。基于这些 结果，我们提出了一个假设，即渗透和抗生素的活性是 受细菌屏障和主动排出的影响不同，这些差异是定义的 通过抗生素的物理化学特性。为了批判性检验这一假设，我们将应用 新的形式和分析铜绿假单胞菌的渗透性屏障的方法， Acinetobacter Baumannii和Burkholderia spp。在组成的组成方面有显着不同 它们的外膜和外排泵。这些病原体实际上是臭名昭著的 难以推广的渗透性障碍。我们的目标是建立结构活动关系 在药物摄取，外排和抑制活性之间，用于精选化合物的库 具有不同渗透率的障碍的上下文。拟议的研究将定义 障碍和化合物的限制，将创建一个框架以优化抗生素 针对“不可渗透”病原体。