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

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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.