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The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis

Award Number: R01AI123146
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: 03/10/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis - Project Summary Pyrazinamide (PZA) is a critical component of first-line tuberculosis (TB) therapy because it has dramatically reduced relapse rates and treatment duration. PZA is weakly active in vitro, but potently sterilizing in vivo, due to its outstanding activity against slow and non-replicating populations of Mycobacterium tuberculosis that are phenotypically tolerant to most other TB drugs. Understanding the basis for the in vivo sterilizing activity of PZA represents one of the most important unmet needs in TB drug discovery. While the mode of action of PZA remains under investigation, our knowledge of factors that govern susceptibility and resistance has advanced considerably in recent years. PZA is a pro-drug that must be converted to the active form of pyrazinoic acid (POA) by the M. tuberculosis amidase PncA, and loss-of-function mutations in pncA account for at least 70% of clinical resistance. Other genetic variations associated with resistance have been described, but most have not been evaluated in isogenic strains to determine their role in resistance, and have not been assessed for association with PZA resistance in animal models of infection. Importantly, PZA lacks antitubercular activity in athymic nude mice, indicating a key role for T cell-mediated immunity in efficacy. Consistent with these observations, our lab and others have shown that PZA is inactive against M. tuberculosis in resting macrophages, but contributes to bacterial killing in macrophages activated by interferon-gamma (IFN-ɣ). Host- dependent stressors that are associated with IFN-ɣ stimulation, such as exposure to low pH, nutrient limitation and reactive oxygen species, have been implicated as contributors to PZA action. Our recent studies have revealed a central role for specific M. tuberculosis stress responses in PZA conditional susceptibility. Through these studies, we have identified a network of functions that modulates PZA susceptibility when expression of the corresponding genes is altered. We have also identified specific host factors that contribute to PZA action in macrophages and in infected mice. Based on these findings, we have identified means to bolster drug action under conditions where PZA typically lacks activity. Through this proposal, we aim to characterize novel molecular mechanisms for PZA resistance, determine host factors that modulate PZA susceptibility, and assess opportunities in host- and microbe-targeted PZA potentiation. These studies will advance our understanding of mechanisms that govern PZA susceptibility and resistance of M. tuberculosis. As a substantial proportion of TB disease results from impaired T cell responses, it is of fundamental importance to understand how these responses relate to PZA efficacy and how we can use this information to optimize PZA action in the context of impaired immunity.


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 = $440,823 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	10	3/25/2025	NON-COMPETING CONTINUATION	$440,823
														Subtotal = $440,823

Issue Date FY: 2024 ( Subtotal = $447,049 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	9	5/23/2024	NON-COMPETING CONTINUATION	$44,705
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	9	2/21/2024	NON-COMPETING CONTINUATION	$402,344
														Subtotal = $447,049

Issue Date FY: 2023 ( Subtotal = $453,149 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	8	2/16/2023	NON-COMPETING CONTINUATION	$453,149
														Subtotal = $453,149

Issue Date FY: 2022 ( Subtotal = $459,133 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	7	2/15/2022	NON-COMPETING CONTINUATION	$459,133
														Subtotal = $459,133

Issue Date FY: 2021 ( Subtotal = $464,000 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	003	6	9/28/2021	COMPETING CONTINUATION	$10,891
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	6	3/10/2021	COMPETING CONTINUATION	$464,000
2021	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	002	5	9/28/2021	NON-COMPETING CONTINUATION	-$10,891
2021	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	5	3/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $464,000

Issue Date FY: 2020 ( Subtotal = $385,000 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	5	1/9/2020	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2019 ( Subtotal = $385,000 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	4	1/10/2019	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2018 ( Subtotal = $469,965 )
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	3	2/15/2018	SUPPLEMENT FOR EXPANSION	$86,006
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	3	1/8/2018	NON-COMPETING CONTINUATION	$383,959
														Subtotal = $469,965

Issue Date FY: 2017 ( Subtotal = $381,458 )
2017	2017	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	2	1/16/2017	NON-COMPETING CONTINUATION	$381,458
														Subtotal = $381,458

Issue Date FY: 2016 ( Subtotal = $380,000 )
2016	2016	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	1/29/2016	NEW	$380,000
														Subtotal = $380,000

Grand Total All Awards = $4,265,577

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The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis

Award Number: R01AI123146

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: 03/10/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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