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Development of Faux-Biotics to combat the spread of hospital-acquired antibiotic-resistant infections

Award Number: F32AI161850
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Development of Faux-Biotics to combat the spread of hospital-acquired antibiotic-resistant infections - Project Summary The CDC considers the escalation of antibiotic resistance to be one of the biggest public health concerns of our time. Antibiotic resistance is a major issue both human and animal health, and resistant infections and resistance genes can be transmitted between animals and the humans who interact with them. One of the most urgent threats is Carbapenem-resistant Enterobacteriaceae (CRE). Antibiotic usage is a major risk factor for the development of fecal CRE carriage, which is both a source of bloodstream infection and spread to other susceptible patients through contact with hospital workers. Due to the lack of treatment options, these infections can be deadly in up to 50% of patients who acquire them. Current therapies to restore colonization resistance target the microbiota using fecal microbiota transplantation, prebiotics, or probiotics. However, for patients who must remain on antibiotics, these treatment options are unlikely to be successful. A healthy microbiota provides colonization resistance in two ways: by occupying all available niches in the intestine to directly prevent other microbiota from colonizing, and through modification of the intestinal environment to make it less welcoming for invading bacteria. The latter includes production of substances such as short-chain fatty acids, which allow the microbiota to interact with host cells and improve intestinal health and colonization resistance. The objective of this application is to devise a treatment to restore colonization resistance during antibiotic therapy that exploit the pathways used by the microbiota under homeostatic conditions. Our hypothesis is that 5-ASA, a drug that activates pathways in colonocytes used by the microbiota, will be successful at restoring colonization resistance against carbapenem resistance Enterobacteriaceae after antibiotic treatment in immunocompetent and immunocompromised hosts. To test our hypothesis, we will first use an SPF mouse model of antibiotic administration and CRE exposure with or without treatment with 5-ASA. Mice will be placed on a 5-ASA-containing diet either prior to CRE exposure (prevention) or after CRE infection (treatment) and colonization will be monitored through feces and cecal contents. We will then infect Germ-free mice recolonized with paired patient fecal samples collected before antibiotics are started and 4-7 days after antibiotic therapy is initiated. These mice will also be placed on a 5-ASA-containing diet to demonstrate that effective prevention or reduction of CRE colonization can be achieved in diverse patient microbiotas with various antibiotic therapies. Finally, we will utilize a cyclophosphamide model of immunosuppression in mice to demonstrate reduced CRE bacteremia as a result of 5-ASA-mediated reduction of intestinal CRE CFU. Successful completion of the proposed research will provide pre-clinical evidence that 5-ASA, a clinically approved drug, can be used to strengthen colonization resistance and lower the risk for CRE bacteremia in an immunocompromised host on antibiotic therapy by activating epithelial PPAR-g signaling, a paradigm shift that establishes the host as a treatment target for strengthening colonization resistance.


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: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	2	3/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $69,802 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	2	5/25/2022	NON-COMPETING CONTINUATION	$69,802
														Subtotal = $69,802

Issue Date FY: 2021 ( Subtotal = $66,390 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	1	3/12/2021	NEW	$66,390
														Subtotal = $66,390

Grand Total All Awards = $136,192

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Development of Faux-Biotics to combat the spread of hospital-acquired antibiotic-resistant infections

Award Number: F32AI161850

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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