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Mechanisms of allostery and molecular recognition in efflux pumps

Award Number: R01AI108889
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: 07/15/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Mechanisms of allostery and molecular recognition in efflux pumps - Project Summary The long-term goals of this project are to uncover molecular mechanisms of antibiotic resistance and to design inhibitors as therapeutics against disease-causing bacteria. Widespread antibiotic resistance among hospital and community associated bacteria, coupled with the lack of new antibiotics, poses an urgent threat to global public health. For these reasons, antibiotic resistance is the silent pandemic, which has been mounting since the introduction of antibiotics in the clinic. The situation is urgent for several pathogens and will become more acute for other pathogenic bacteria in the coming years. There is no magic bullet solution to solve the antibiotic resistance problem; rather, a concerted effort is required that includes new antibiotics, tackling resistance mechanisms head-on, and better stewardship of antibiotics and antiseptics. Bacteria possess several mechanisms to confer resistance to the host organism, including modification of the antibiotic, mutation to the target site, reduced uptake of antibiotics, and the presence of membrane protein efflux pumps. This proposal is aimed at understanding molecular mechanisms of efflux, which is a first-line resistance mechanism used by bacteria to lower the intracellular drug concentration, thereby facilitating pathogen survival. Inhibitors of efflux pumps have therapeutic potential as antibiotic adjuvants by directly targeting a central mechanism of resistance in pathogenic bacteria. However, the lack of clinically approved efflux pump inhibitors underscores a key challenge in the field: how to design specific inhibitors of a substrate binding pocket that promiscuously binds structurally diverse drugs? We recently uncovered a promising solution to this problem through the discovery of antibody inhibitors to B. subtilis Bmr and S. aureus NorA where a loop inserts into the substrate binding pocket. We hypothesize the substrate binding pockets of transporters can be systematically targeted for inhibition by peptide mimics of the antibody paratope. By using efflux pumps within the Bacillus genus, Bmr and Blt, this proposal will probe how efflux pumps recognize multiple substrates (Aim 1), will reveal cryptic pockets within the substrate binding pocket of efflux pumps by using antibodies as tools (Aim 2), and develop a systematic approach for creating conformationally defined mimics of the antibody b-hairpin paratope (Aim 3). Since Bmr and Blt share ~80% sequence homology yet display different substrate specificities, this system serves as a good comparative group for determining whether transporter-selective inhibitors can be designed. The approaches developed in this grant will establish the long-term viability of novel efflux pump inhibitors to the treatment of antibiotic resistant organisms.


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 = $1,076,094 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	002	11	6/10/2025	NON-COMPETING CONTINUATION	$538,047
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	001	10	2/25/2025	COMPETING CONTINUATION	$538,047
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	001	10	2/25/2025	COMPETING CONTINUATION	$189
2025	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	9	2/25/2025	NON-COMPETING CONTINUATION	-$189
														Subtotal = $1,076,094

Issue Date FY: 2024 ( Subtotal = $553,297 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	10	7/5/2024	COMPETING CONTINUATION	$553,297
														Subtotal = $553,297

Issue Date FY: 2023 ( Subtotal = $444,895 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	9	7/26/2023	NON-COMPETING CONTINUATION	$444,895
														Subtotal = $444,895

Issue Date FY: 2022 ( Subtotal = $453,581 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	8	7/15/2022	NON-COMPETING CONTINUATION	$453,581
														Subtotal = $453,581

Issue Date FY: 2021 ( Subtotal = $462,059 )
2021	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	002	7	7/15/2021	NON-COMPETING CONTINUATION	$462,059
2021	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	7/6/2021	COMPETING CONTINUATION	$52
2021	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	7/6/2021	NON-COMPETING CONTINUATION	-$52
														Subtotal = $462,059

Issue Date FY: 2020 ( Subtotal = $455,025 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	6	7/27/2020	COMPETING CONTINUATION	$455,025
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	8/4/2020	COMPETING CONTINUATION	$0
														Subtotal = $455,025

Issue Date FY: 2018 ( Subtotal = $388,149 )
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	6/21/2018	NON-COMPETING CONTINUATION	$388,149
														Subtotal = $388,149

Issue Date FY: 2017 ( Subtotal = $388,385 )
2017	2017	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	7/1/2017	NON-COMPETING CONTINUATION	$388,385
														Subtotal = $388,385

Issue Date FY: 2016 ( Subtotal = $388,614 )
2016	2016	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	6/8/2016	NON-COMPETING CONTINUATION	$388,614
														Subtotal = $388,614

Issue Date FY: 2015 ( Subtotal = $388,836 )
2015	2015	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	6/23/2015	NON-COMPETING CONTINUATION	$388,836
														Subtotal = $388,836

Issue Date FY: 2014 ( Subtotal = $388,441 )
2014	2014	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	6/30/2014	NEW	$388,441
														Subtotal = $388,441

Grand Total All Awards = $5,387,376

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Mechanisms of allostery and molecular recognition in efflux pumps

Award Number: R01AI108889

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: 07/15/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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