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Plugging & Pulling-in: tuning peptides for ToIC to overcome anitbiotic resistance

Award Number: R01GM148583
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Plugging & Pulling-in: tuning peptides for ToIC to overcome anitbiotic resistance - Plugging & Pulling-in: tuning peptides for TolC to overcome antibiotic resistance Summary Antibiotic resistant infections already kill more people per year than HIV/AIDS or malaria. Clinical antibiotic resistance is correlated with the overexpression of particular efflux pumps. These efflux pumps shuttle out most classes of antibiotics so that the antibiotics can’t reach their targets, reducing their effectiveness. The most accessible part of the efflux pump is its outer membrane barrel. The outer membrane barrel accessibility makes it a good target for pharmaceutical development because it can be accessed without getting through the often impermeable outer membrane. The efflux pump presents as both a possible target for stopping antibiotic efflux and a possible avenue of drug delivery. Plugging efflux pumps would make the antibiotics we already have work like new by stopping antibiotics from being removed from the cell and allowing them to reach their targets. Hijacking the barrel for cellular import could be used to deliver drugs that otherwise could not cross the bacterial outer membrane. Our long term goal is to develop peptides to combat antibiotic resistant infection. The objective of the proposed research is to determine 1) what protein-protein interactions are necessary to create high affinity plugs and 2) what protein-protein interactions can facilitate peptide transit through the pump. We have recently solved the first structure of an exogenous protein binding the outer membrane barrel of the E. coli antibiotic resistance. It is an unusual helix-in-barrel structure. We have shown that the binding of this protein has some ability to act as a plug. It stops efflux and make antibiotics more potent. We have also created databases of outer membrane barrels to better understand the sequence structure relationships in these proteins. Here we propose to leverage these past successes to 1) Identify common sequence and structural barrel-peptide interactions for antibiotic efflux pump-like proteins 2) Screen for peptides that bind well to the E. coli antibiotic efflux pump and identify the features that determine that binding, and 3) Identify what would facilitate the translocation of proteins across the efflux pump that otherwise bind to the efflux pump. The global concept of this work, creating new plugs and translocators for membrane β-barrels, has, to our knowledge, never been done before. The expected outcomes of these experiments are a knowledge of how protein-protein interactions facilitate plugging and pulling through of antibiotic efflux pumps, as well as the creation of peptides that plug or pull through TolC. This work is poised to make a significant contribution because it will demonstrate the important protein-protein interactions necessary to create membrane protein plugs and translocators and can thereby enable a revival of existing antibiotics against resistant superbugs.


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 = $314,094 )
2025	2025	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Biomedical Research and Research Training	000	3	7/22/2025	NON-COMPETING CONTINUATION	$314,094
														Subtotal = $314,094

Issue Date FY: 2024 ( Subtotal = $367,962 )
2024	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Biomedical Research and Research Training	000	2	7/17/2024	NON-COMPETING CONTINUATION	$302,962
2024	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Biomedical Research and Research Training	001	2	8/27/2024	SUPPLEMENT FOR EXPANSION	$65,000
														Subtotal = $367,962

Issue Date FY: 2023 ( Subtotal = $311,242 )
2023	2023	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Biomedical Research and Research Training	000	1	7/26/2023	NEW	$311,242
														Subtotal = $311,242

Grand Total All Awards = $993,298

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Plugging & Pulling-in: tuning peptides for ToIC to overcome anitbiotic resistance

Award Number: R01GM148583

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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