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Infection-Dependent Vulnerabilities of Gram-negative Bacterial Pathogens

Award Number: R01AI168916
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: 08/07/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Infection-Dependent Vulnerabilities of Gram-negative Bacterial Pathogens - SUMMARY The larger goal of the project is to identify infection-dependent weaknesses of Gram-negative bacterial pathogens that could be exploited chemically. We focus on the human pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) and its survival within mammalian cells and use cell culture infection models and small molecules as tools. We and others have observed that some small molecules that are not effective against Gram-negative bacteria in media prevent pathogen survival during infection of cells and animals. Gram-negative bacteria likely become vulnerable during infection to small molecules because a variety of host innate immune mechanisms permeabilize the bacterial cell envelope and/or occupy efflux pumps, enabling compounds to reach a periplasmic or cellular target. When laboratory media imitates host innate immunity by permeabilizing the outer membrane, these compounds inhibit bacterial growth. We have identified small molecules that under broth conditions that permeabilize the outer membrane or in protoplasts, dissipate bacterial inner membrane voltage without physically disrupting the lipid bilayer. Membrane voltage disruption could compromise bacteria by, for instance, interfering with energy production and/or activating stress- response signaling. The compounds do not disrupt mammalian membranes at concentrations that kill S. Typhimurium in macrophages and at least one of the compounds reduces tissue colonization in mice, demonstrating in vivo potential for this approach. The Specific Aims will interrogate five distinct molecule classes to determine whether targeting the inner membrane should be pursued as a novel approach to fighting Gram-negative bacterial infections.


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 = $590,687 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	003	3	8/8/2025	SUPPLEMENT FOR EXPANSION	$132,153
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	002	3	8/5/2025	NON-COMPETING CONTINUATION	$458,534
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	001	2	7/11/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	000	2	4/21/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $590,687

Issue Date FY: 2024 ( Subtotal = $653,946 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	002	2	7/24/2024	SUPPLEMENT FOR EXPANSION	$132,253
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	000	1	3/21/2024	SUPPLEMENT FOR EXPANSION	$45,944
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	001	2	7/23/2024	NON-COMPETING CONTINUATION	$475,749
														Subtotal = $653,946

Issue Date FY: 2023 ( Subtotal = $508,711 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Allergy and Infectious Diseases Research	000	1	8/7/2023	NEW	$508,711
														Subtotal = $508,711

Grand Total All Awards = $1,753,344

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Infection-Dependent Vulnerabilities of Gram-negative Bacterial Pathogens

Award Number: R01AI168916

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: 08/07/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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