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Development of Drugs to Target Arginine Biosythesis in Mycobacterium tuberculosis

Award Number: SC1GM140968
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: 04/22/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Development of Drugs to Target Arginine Biosythesis in Mycobacterium tuberculosis - SUMMARY Tuberculosis (TB) remains a significant global health problem causing 10 million new cases and 1.2 million deaths just last year according to the World Health Organization (WHO). The single greatest impediment to TB control is its ability to form persisters, the subpopulation of Mycobacterium tuberculosis (Mtb) cells that are phenotypically resistant to killing by bactericidal drugs or immune effectors. We have discovered that arginine starvation, induced by inoculating mutants of Mtb cells into arginine-free media or mice, mediates rapid sterilization that kills both actively growing Mtb cells and Mtb persister cells both in vitro and in vivo. Moreover, we have successfully determined the structure of the Mtb ArgB enzyme and used Fragment-Based Drug Discovery (FBDD) to discover two scaffold compounds that bind and inhibit the enzymatic activity of ArgB. The absence of the de novo arginine biosynthesis pathway enzymes Arg A, B, C, D, and J in humans and our demonstration that Mtb cannot bypass argB or argF deletions make Arginine Biosynthetic Enzymes attractive drug targets for TB drug development. Transcriptomic, metabolomics and flow-cytometric analyses on the arginine starving cells have provided new insights into the sterilization process. By comparing arginine starvation to three other sterilizing regimens, we identified a set of six genes that provide a sterilization signature. We plan to exploit these genes for improved drug discovery, by identifying novel drugs to inhibit the activity of Mtb ArgB using fragment-based drug design, confirm genetically any additional targets of the arginine biosynthetic pathway to expand the drug target space, and determining the correlative or causative role the common sterilizing signature genes play in Mtb sterilization. Together these studies will make available a new way to rapidly sterilize cultures of Mtb and provide new drug possibilities and new insights to shorten TB chemotherapy and treat drug-resistant TB.


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: 2026 ( Subtotal = $0 )
2026	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Biomedical Research and Research Training	000	4	5/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $377,500 )
2024	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Biomedical Research and Research Training	000	4	3/27/2024	NON-COMPETING CONTINUATION	$339,750
2024	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Biomedical Research and Research Training	001	4	6/18/2024	NON-COMPETING CONTINUATION	$37,750
														Subtotal = $377,500

Issue Date FY: 2023 ( Subtotal = $377,500 )
2023	2023	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Biomedical Research and Research Training	000	3	3/28/2023	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2022 ( Subtotal = $377,500 )
2022	2022	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Biomedical Research and Research Training	000	2	3/10/2022	NON-COMPETING CONTINUATION	$339,750
2022	2022	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Biomedical Research and Research Training	001	2	6/14/2022	NON-COMPETING CONTINUATION	$37,750
														Subtotal = $377,500

Issue Date FY: 2021 ( Subtotal = $377,500 )
2021	2021	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Biomedical Research and Research Training	000	1	4/22/2021	NEW	$377,500
														Subtotal = $377,500

Grand Total All Awards = $1,510,000

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Development of Drugs to Target Arginine Biosythesis in Mycobacterium tuberculosis

Award Number: SC1GM140968

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: 04/22/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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