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Transport Mechanisms and Inhibition of Efflux Pumps in Pathogenic Organisms

Award Number: R01AI165782
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 08/03/2025

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Transport Mechanisms and Inhibition of Efflux Pumps in Pathogenic Organisms - Project Summary The long-term goal of our research is to develop first-in-class, protein-based inhibitors against human bacterial pathogens by directly blocking efflux pumps. Drug resistant bacteria pose an urgent global health challenge by reducing the effectiveness of antibiotics used to treat infections in humans and animals. The broadest resistance mechanism against antibiotics are efflux pumps, which transport drugs out of the cytoplasm and reduce toxicity to the organism. While it is known that efflux pumps display broad specificity to structurally distinct compounds, the mechanisms of polyspecific drug binding and ion-coupled transport remain unanswered questions in the field. Given the promiscuity of efflux pump binding to structurally distinct drugs, it is also unclear whether potent and selective efflux pump inhibitors can be designed to target specific classes of efflux pumps. The specific goals of this project are to discover novel mechanisms of active transport in drug resistant Staphylococcus aureus and to harness this knowledge to design selective inhibitors toward efflux pumps. Our proposal is strongly motivated by our recent discovery of antibody fragments (Fabs) that bind the Staphylococcus aureus efflux pump NorA and successful determination of high-resolution cryoEM structures using the Fabs as fiduciaries. The structures revealed that the Fabs insert a loop into the substrate binding pocket from the extracellular side, which suggests a design path toward protein- and peptide-based inhibitors. This interaction is facilitated by an electrostatic interaction between a positively charged arginine on the Fab and two essential anionic residues within NorA. Building on these preliminary data, we propose to carry out four Specific Aims. Aim 1 will develop a hybrid approach of cryo-electron microscopy and NMR spectroscopy to comprehensively study the transport cycle of NorA. Aim 2 will seek to determine the molecular basis for polyspecific drug binding. Aim 3 will design and characterize protein-based inhibitors that target the accessible, outward-open conformation of NorA. Aim 4 will develop peptides that miniaturize the antibody loops observed in the binding pocket of NorA. We have assembled an interdisciplinary team with expertise in structural biology, protein engineering, microbiology, chemical synthesis, and computational chemistry to rapidly answer fundamental questions about multidrug transport and inhibition of efflux pumps. All of the approaches applied to NorA will be translatable to other transporter systems.


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: 2026 ( Subtotal = $813,289 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	5	1/22/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$813,289
2026	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	1/22/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $813,289

Issue Date FY: 2025 ( Subtotal = $831,606 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	11/21/2024	NON-COMPETING CONTINUATION	$743,532
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	11/22/2024	SUPPLEMENT FOR EXPANSION	$88,074
														Subtotal = $831,606

Issue Date FY: 2024 ( Subtotal = $816,928 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	001	3	2/27/2024	SUPPLEMENT FOR EXPANSION	$73,396
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	003	3	9/3/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	002	3	5/15/2024	NON-COMPETING CONTINUATION	$74,354
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	10/31/2023	NON-COMPETING CONTINUATION	$669,178
														Subtotal = $816,928

Issue Date FY: 2023 ( Subtotal = $743,532 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	12/1/2022	NON-COMPETING CONTINUATION	$743,532
														Subtotal = $743,532

Issue Date FY: 2022 ( Subtotal = $743,532 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	11/22/2021	NEW	$743,532
														Subtotal = $743,532

Grand Total All Awards = $3,948,887

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Transport Mechanisms and Inhibition of Efflux Pumps in Pathogenic Organisms

Award Number: R01AI165782

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 08/03/2025

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