Thursday, July 3, 2025 7/3/2025

Using bile salt metabolism to modulate CDI prophylaxis

Award Number: R01AI109139
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: 12/01/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2025

Group Awards By:

View Award Description

Using bile salt metabolism to modulate CDI prophylaxis - Abstract Clostridium difficile infection (CDI) is the main identifiable cause of antibiotic assoicated diarreah. in the US alone, there are close to 500,000 cases annually causing approximately 25,000 deaths and costs the health care system an estimated $6.3 billion. C. difficile spores do not cause disease but can revert to toxin-producing bacteria (a process called germination) in the microbiota-depleted gut of hospitalized patients. We found that synthetic cholan-24-amides inhibit C. difficile spore germination and, more importantly, protects rodents from CDI without toxic effects. While amide-linked bile salts have many attractive properties, their hydrolysis can release toxic byproducts. To address this liability, we developed heterobicyclic non-hydrolysable bile salts (NHBS) as anti- germinants. Importantly, two analogs protect mice from CDI and are stable to the gut microbiome. This R01 renewal is based on five foundational discoveries obtained during the last funding period: (I) Optimized pipeline for CDI prophylactic development, (ii) synthetic bile salt analogs can be uptaked by the host’s enterohepatic circulation (EHC), (iii) bile salt analogs can be modified by the gut microbiota, Bile salt side chain integrity and hydroxylation state influence anti-germination activity and/or CDI prophylaxis, and (v) NHBS analogs are stable towards the gut microbiome, have anti-germination activity against hypervirulent C. difficile spores, and can protect mice from CDI. Based on the sum of these discoveries, we hypothesize that the anti-germination and CDI prophylaxis activities of new NHBS analogs can be modulated by the combined metabolic action of the EHC and the gut microbiota. To achieve these goal, we will: (1) Synthesize libraries of NHBS analogs, (2) characterize the binding sites of anti-germinant binding proteins, (3) determine in vitro efficacy, permeability, stability, and toxicity of NHBS analogs, (4) assess pharmacokinetic parameters of selected NHBS analogs, and (5) determine the pharmacodynamics of CDI prophylactics on bile salt homeostasis At the start of this project, we will finish characterizing our lead NHBS. This data will provide benchmarks for new analogs. Our medicinal chemistry efforts will be initially guided by germination activity, but subsequent identification of NHBS binding sites could aid this effort. As in vitro and in vivo data is obtained, GO/NO GO criteria will eliminate sub-optimal analogs and inform the rational synthesis of more potent and stable anti-germinants. This iterative process will be continued until at least one optimized CDI prophylactic is obtained. As a secondary goal, we will develop CDI prophylactic dosages that can match the heterogenicity of human CDI risk and variable antibiotic regimes.


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 = $0 )
2025	2024	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	6	4/18/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $739,487 )
2024	2024	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	6	8/9/2024	COMPETING CONTINUATION	$739,487
														Subtotal = $739,487

Issue Date FY: 2022 ( Subtotal = -$5,123 )
2022	2019	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	5	7/18/2022	NON-COMPETING CONTINUATION	-$5,123
														Subtotal = -$5,123

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	5	2/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $639,084 )
2019	2019	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	5	11/19/2018	NON-COMPETING CONTINUATION	$639,084
														Subtotal = $639,084

Issue Date FY: 2018 ( Subtotal = $639,084 )
2018	2018	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	4	11/21/2017	NON-COMPETING CONTINUATION	$639,084
														Subtotal = $639,084

Issue Date FY: 2017 ( Subtotal = $639,084 )
2017	2017	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	3	11/28/2016	NON-COMPETING CONTINUATION	$639,084
														Subtotal = $639,084

Issue Date FY: 2016 ( Subtotal = $639,084 )
2016	2016	UNIVERSITY OF NEVADA-LAS VEGAS	4505 S MARYLAND PWY BOX 451005	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	2	11/27/2015	NON-COMPETING CONTINUATION	$639,084
														Subtotal = $639,084

Issue Date FY: 2015 ( Subtotal = $692,240 )
2015	2015	UNIVERSITY OF NEVADA-LAS VEGAS	4505 S MARYLAND PWY BOX 451005	LAS VEGAS	NV	89154	CLARK	USA	Allergy and Infectious Diseases Research	000	1	11/13/2014	NEW	$692,240
														Subtotal = $692,240

Grand Total All Awards = $3,982,940

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Using bile salt metabolism to modulate CDI prophylaxis

Award Number: R01AI109139

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: 12/01/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer