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

革兰氏阴性杆菌的通透性障碍及绕过途径 他们 革兰氏阴性菌的一个主要耐药性来源是由 抗生素通过外膜缓慢吸收和主动外排的协同作用。这个 拟议的研究将解决了解细胞渗透的关键需求 革兰氏阴性菌的包膜及研制抗革兰阴性菌的抗生素 病原体。在初步研究中，我们建立了新的数学和经验方法 分析具有主动外排的两层膜屏障的药物摄取。基于这些 结果，我们提出了一个假设，即抗生素的渗透性和活性是 受细菌屏障和主动外排的影响不同，这些差异被定义为 通过抗生素的物理化学性质。为了批判性地检验这一假设，我们将应用 分析铜绿假单胞菌通透性屏障的新理论和新方法， 鲍曼不动杆菌和伯克霍尔德氏菌。在组成上有很大的不同 它们的外膜和外排泵。这些病原体是臭名昭著的 坚不可摧的渗透屏障。我们的目标是建立结构-活动关系 药物摄取、外排和抑制活性之间的关系 具有不同渗透性特性的屏障的背景。建议的研究将界定 限制屏障和化合物，并将创建一个优化抗生素的框架 瞄准“不透水”的病原体。

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.