Thursday, November 21, 2024 11/21/2024

Transport across two membranes by AcrAB-TolC

Award Number: R01AI052293
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Description Multidrug efflux pumps as exemplified by AcrAB-TolC from Escherichia coli are the major contributors to clinical antibiotic resistance in bacteria and to various adaptive responses during pathogenesis and chronic infections. During the previous funding period, we made major advances in two areas: 1) understanding the molecular mechanism of efflux pump assembly and the role of periplasmic membrane fusion proteins in multidrug efflux across two membranes; and 2) the development of a synergistic computational and empirical approach to discovering efflux pump inhibitors with novel mechanisms of action. We successfully applied these advances to discover inhibitors that act in a novel way, by interacting with AcrA and inhibiting the assembly of the AcrAB- TolC complex. These efflux pump inhibitors potentiate activities of multiple antibiotics in various bacteria. The major goal of the proposed research is to establish the molecular mechanisms of the new efflux pump inhibitors and to optimize these inhibitors for use in combination with specific antibiotics and against specific multidrug resistant bacteria. The underlying hypothesis is that the broad potentiation activity of the discovered inhibitors is caused by their unique mechanism that traps efflux pumps in a poorly assembled and leaky conformation. In the proposed approach, biochemical, structural and kinetic experiments will be used synergistically with advanced computations to characterize the mechanism of efflux pump inhibitors and to optimize inhibitors acting on efflux pumps of multidrug resistant Acinetobacter baumannii. To optimize inhibitors, we will apply what is to our knowledge the most comprehensive platform available. The platform utilizes a set of strains with variable efflux capacities and outer membrane permeability barriers and allows to establish structure-activity relationships separately for efflux avoidance, inhibition and permeation across the outer membrane. Successful completion of the proposed experiments will help design efflux pump inhibitors that would be effective even in the context of multiple pumps and mechanisms of antibiotic resistance.


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: 2024 ( Subtotal = $493,895 )
2024	2024	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	20	3/15/2024	NON-COMPETING CONTINUATION	$493,895
														Subtotal = $493,895

Issue Date FY: 2023 ( Subtotal = $493,885 )
2023	2023	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	19	3/28/2023	NON-COMPETING CONTINUATION	$493,885
														Subtotal = $493,885

Issue Date FY: 2022 ( Subtotal = $493,878 )
2022	2022	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	18	3/16/2022	NON-COMPETING CONTINUATION	$493,878
														Subtotal = $493,878

Issue Date FY: 2021 ( Subtotal = $493,833 )
2021	2021	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	17	3/25/2021	NON-COMPETING CONTINUATION	$493,833
2021	2020	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	002	16	7/19/2021	COMPETING CONTINUATION	$202,100
2021	2018	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	001	15	7/19/2021	NON-COMPETING CONTINUATION	-$202,100
														Subtotal = $493,833

Issue Date FY: 2020 ( Subtotal = $548,670 )
2020	2020	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	002	16	6/4/2020	COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	001	16	4/2/2020	COMPETING CONTINUATION	$548,670
2020	2018	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	15	3/25/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $548,670

Issue Date FY: 2018 ( Subtotal = $407,274 )
2018	2018	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	15	7/30/2018	NON-COMPETING CONTINUATION	$407,274
														Subtotal = $407,274

Issue Date FY: 2017 ( Subtotal = $418,105 )
2017	2017	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	14	7/27/2017	NON-COMPETING CONTINUATION	$418,105
2017	2016	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	002	13	8/10/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$3,976
2017	2015	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	001	12	8/10/2017	NON-COMPETING CONTINUATION	-$3,976
														Subtotal = $418,105

Issue Date FY: 2016 ( Subtotal = $427,085 )
2016	2016	UNIVERSITY OF OKLAHOMA	201 STEPHENSON PARKWAY	NORMAN	OK	73019	CLEVELAND	USA	Allergy and Infectious Diseases Research	000	13	7/11/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$427,085
														Subtotal = $427,085

Issue Date FY: 2015 ( Subtotal = $423,849 )
2015	2015	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	12	7/2/2015	NON-COMPETING CONTINUATION	$423,849
														Subtotal = $423,849

Issue Date FY: 2014 ( Subtotal = $441,603 )
2014	2014	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	001	11	7/29/2014	COMPETING CONTINUATION	$441,603
2014	2013	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	10	7/24/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $441,603

Issue Date FY: 2013 ( Subtotal = $341,091 )
2013	2013	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	10	11/29/2012	NON-COMPETING CONTINUATION	$326,576
2013	2013	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	001	10	6/6/2013	NON-COMPETING CONTINUATION	$14,515
														Subtotal = $341,091

Issue Date FY: 2012 ( Subtotal = $362,999 )
2012	2012	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	001	9	5/25/2012	NON-COMPETING CONTINUATION	$36,300
2012	2012	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	9	11/17/2011	NON-COMPETING CONTINUATION	$326,699
														Subtotal = $362,999

Issue Date FY: 2011 ( Subtotal = $363,132 )
2011	2011	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	001	8	6/6/2011	NON-COMPETING CONTINUATION	$33,012
2011	2011	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	8	11/22/2010	NON-COMPETING CONTINUATION	$330,120
														Subtotal = $363,132

Issue Date FY: 2010 ( Subtotal = $366,928 )
2010	2010	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	7	11/23/2009	NON-COMPETING CONTINUATION	$333,571
2010	2010	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	001	7	5/26/2010	NON-COMPETING CONTINUATION	$33,357
														Subtotal = $366,928

Issue Date FY: 2009 ( Subtotal = $217,048 )
2009	2009	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	6	12/12/2008	COMPETING CONTINUATION	$217,048
														Subtotal = $217,048

Issue Date FY: 2007 ( Subtotal = $275,920 )
2007	2007	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	5	3/7/2007	NON-COMPETING CONTINUATION	$275,920
														Subtotal = $275,920

Issue Date FY: 2006 ( Subtotal = $284,162 )
2006	2006	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Allergy and Infectious Diseases Research	000	4	3/6/2006	NON-COMPETING CONTINUATION	$284,162
														Subtotal = $284,162

Issue Date FY: 2005 ( Subtotal = $291,000 )
2005	2005	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	1000 ASP AVENUE	NORMAN	OK	73109		USA	Microbiology and Infectious Diseases Research	000	3	3/1/2005	NON-COMPETING CONTINUATION	$291,000
														Subtotal = $291,000

Issue Date FY: 2004 ( Subtotal = $291,000 )
2004	2004	UNIVERSITY OF OKLAHOMA NORMAN CAMPUS	555 CONSTITUTION ST., STE. 237	NORMAN	OK	73072	CLEVELAND	USA	Microbiology and Infectious Diseases Research	000	2	3/4/2004	NON-COMPETING CONTINUATION	$291,000
														Subtotal = $291,000

Issue Date FY: 2003 ( Subtotal = $271,435 ) (Continued on the next page)
Grand Total All Awards = $7,706,792

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Transport across two membranes by AcrAB-TolC

Award Number: R01AI052293

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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