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Defining Host-pathogen Interactions in CAUTI to Guide Novel Drug Development

Award Number: K01DK128381
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Defining Host-pathogen Interactions in CAUTI to Guide Novel Drug Development - PPROJECT ABSTRACT More than 30 million urinary catheters (UCs) are placed every year in the US, making them the most commonly used indwelling medical device. While short-term UC usage is common in hospitals as part of standard patient care, chronic indwelling UCs are frequently used outside the healthcare system to improve the quality of life of individuals with urinary tract abnormalities, such as incontinence and neurogenic bladder. UCs are associated with high infection rates, particularly among patients with chronic indwelling UCs. Furthermore, catheter- associated urinary tract infections (CAUTIs) can result in severe morbidity and increased mortality. CAUTI caused by bacteria with high pathogenic potential such as Staphylococcus aureus, pose additional challenges in chronically catheterized individuals. Additionally, our preliminary data suggest that S. aureus strains that cause CAUTI produce urease. This enzyme contributes to the formation of UC encrustations, which are particularly recalcitrant to treatment and lead to device failure. Thus, to gain a better understanding of the mechanisms that facilitate these common infections and inform the development of effective prevention or treatment strategies, this proposal seeks to investigate the functional and genomic role of urease in S. aureus CAUTI. My preliminary data suggest S. aureus urease is part of the carbon catabolite protein (CcpA) regulon and contributes to CAUTI during short UC dwell times. Furthermore, I have identified small molecule compounds that directly interact with the urease holoenzyme, suggesting these molecules can be optimized to develop anti-virulence therapies that inhibit urease activity and may be used to treat CAUTI caused by S. aureus or other urease-producing uropathogens. I postulate that urease is essential for chronic S. aureus CAUTI and that the enzyme is regulated as part of the CcpA regulon. Furthermore, I hypothesize that the increase in enzymatic activity observed in S. aureus strains serially collected from chronically catheterized and colonized individuals is dictated by single nucleotide polymorphisms within the regulatory elements and/or the urease operon. Using a robust collection of clinically relevant S. aureus strains recently isolated from individuals with chronic UCs, I will investigate the mechanisms that facilitate S. aureus CAUTI in three specific aims. First, I will examine the conserved genomic features and define the regulatory elements that affect S. aureus urease expression and activity. Second, I will determine the role of urease in chronic S. aureus CAUTI. Finally, I will optimize anti-virulence compounds that inhibit this enzyme. These findings may provide the insights needed to develop non-antibiotic interventions that treat recalcitrant CAUTIs and support the career development of a translational scientist focused on UTIs. The University of Texas Health Science Center and Texas Medical Center has a nationally recognized research program that offers an exceptional environment to conduct my research and receive the training needed to transition to independence.


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 = $137,938 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/25/2024	NON-COMPETING CONTINUATION	$137,938
														Subtotal = $137,938

Issue Date FY: 2024 ( Subtotal = $137,938 )
2024	2024	UNIVERSITY OF HEALTH SCIENCE CENTER	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/15/2023	NON-COMPETING CONTINUATION	$137,938
														Subtotal = $137,938

Issue Date FY: 2023 ( Subtotal = $137,778 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/28/2022	NON-COMPETING CONTINUATION	$137,778
														Subtotal = $137,778

Issue Date FY: 2022 ( Subtotal = $139,278 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/22/2021	NEW	$139,278
														Subtotal = $139,278

Grand Total All Awards = $552,932

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Defining Host-pathogen Interactions in CAUTI to Guide Novel Drug Development

Award Number: K01DK128381

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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