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

Award Number: R01AI132836
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/08/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $455,323 )
2025	2025	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	8	3/31/2025	NON-COMPETING CONTINUATION	$455,323
														Subtotal = $455,323

Issue Date FY: 2024 ( Subtotal = $463,073 )
2024	2024	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	7	4/16/2024	NON-COMPETING CONTINUATION	$463,073
														Subtotal = $463,073

Issue Date FY: 2023 ( Subtotal = $463,073 )
2023	2023	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	6	4/19/2023	NON-COMPETING CONTINUATION	$463,073
2023	2022	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	002	5	6/23/2023	COMPETING CONTINUATION	$139,832
2023	2020	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	001	4	6/23/2023	NON-COMPETING CONTINUATION	-$139,832
														Subtotal = $463,073

Issue Date FY: 2022 ( Subtotal = $463,073 )
2022	2022	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	5	5/12/2022	COMPETING CONTINUATION	$463,073
														Subtotal = $463,073

Issue Date FY: 2020 ( Subtotal = $498,640 )
2020	2020	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	4	4/8/2020	NON-COMPETING CONTINUATION	$498,640
														Subtotal = $498,640

Issue Date FY: 2019 ( Subtotal = $498,640 )
2019	2019	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	3	4/12/2019	NON-COMPETING CONTINUATION	$498,640
														Subtotal = $498,640

Issue Date FY: 2018 ( Subtotal = $514,140 )
2018	2018	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	2	4/13/2018	NON-COMPETING CONTINUATION	$514,140
														Subtotal = $514,140

Issue Date FY: 2017 ( Subtotal = $518,640 )
2017	2017	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	1	5/5/2017	NEW	$518,640
														Subtotal = $518,640

Grand Total All Awards = $3,874,602

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

Award Number: R01AI132836

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/08/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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