Permeability barriers of Gram-negative pathogens and approaches to bypass them

项目说明 对革兰氏阴性病原体有效的抗生素是尚未得到满足的需求的关键领域。由以下原因引起的感染 这些病原体不仅难以治疗，而且还能找到克服革兰氏阴性耐药性的新疗法。 也是一个挑战。抗生素研发渠道中的主要障碍是缺乏对如何突破 这些病原体的抗生素渗透屏障。此外，这些渗透障碍是主要的 临床环境中的抗生素耐药机制。该项目的长期目标是建立 药物摄取、外排和抗生素抑制活性之间的构效关系 具有不同性质的渗透屏障。在上一次筹资期间，我们取得了重大进展 在理解外排泵和细胞膜之间的功能和调节相互作用方面 铜绿假单胞菌、鲍曼不动杆菌和泰兰伯克霍尔德菌。这些病原体是 因其几乎无法突破的渗透屏障而臭名昭著，并了解这些屏障如何 渗透是成功开发新疗法和有效管理新兴疗法的关键 抗生素耐药性。这个应用程序的主要目标是表征表达式中的变化 外排泵的功能与细菌生理学以及药物渗透性障碍是如何结合的 在细菌感染期间进行了修改。为了实现这一目标，我们将分析外排泵之间的关系 以及差异显著的铜绿假单胞菌、鲍曼不动杆菌和泰兰杆菌的通透性障碍 在它们的外膜和外排泵的组成中。接下来，我们将把这些关系扩展到 细菌-宿主细胞界面，并将决定细菌感染如何影响药物在两种细菌之间的流动 和宿主细胞膜。

Project Description Antibiotics effective against Gram-negative pathogens are a critical area of unmet need. Infections caused by these pathogens are not only difficult to treat but finding new therapies to overcome Gram-negative resistance is also a challenge. The major obstacle in antibiotic discovery pipeline is the lack of understanding how to breach antibiotic permeability barriers of these pathogens. Furthermore, these permeability barriers are one of the major resistance mechanisms to antibiotics in clinical settings. The long-term goal of this project is to establish structure-activity relationships between drug uptake, efflux and inhibitory activities of antibiotics in the context of permeation barriers with different properties. During the previous funding period, we made significant progress in understanding the functional and regulatory interactions between efflux pumps and cellular membranes in Pseudomonas aeruginosa, Acinetobacter baumannii and Burkholderia thailandensis. These pathogens are notorious for their virtually unbreachable permeability barriers and understanding how these barriers can be penetrated is critical for successful development of new therapeutics and for effective management of emerging antibiotic resistance. The major objective of this application is to characterize how changes in the expression and functions of efflux pumps are integrated into bacterial physiology and how drug permeability barriers are modified during bacterial infections. To achieve this objective, we will analyze relationships between efflux pumps and permeability barriers in P. aeruginosa, A. baumannii and B. thailandensis pathogens that differ significantly in the composition of their outer membranes and efflux pumps. We will next extend these relationships into the bacteria-host cell interface and will determine how bacterial infections affects drug fluxes across both bacterial and host cell membranes.