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Repurposing antimalarials for the treatment of NTM infections

Award Number: R01AI170504
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: 06/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Repurposing antimalarials for the treatment of NTM infections - Abstract The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections caused by Mycobacterium abscessus complex (MABSC) and Mycobacterium avium complex (MAC) species is increasing worldwide and poses a particular threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. The intrinsic recalcitrance of these pathogens to chemotherapeutic treatments and alarming treatment failure rates place a high priority on the development of more effective treatment approaches. The ability of MABSC and MAC to persist intracellularly and extracellularly within granulomatous lesions in a non-replicating state is likely to contribute to the drug tolerance of these microorganisms and to treatment failure in chronically-infected individuals. Further compounding this problem is the ability of MABSC and MAC to form what appears to be genetically programmed biofilms during human pulmonary infections. A common stress faced by intra- and extracellular NTM inside activated immune cells, in avascular necrotic and caseous regions of granulomas, and within microaggregates or biofilms is the inhibition of aerobic respiration caused by O2 depletion or exposure to nitric oxide (NO) and carbon monoxide. M. tuberculosis (Mtb) is known to survive this stress by inducing a regulon of ~50 genes that drives the entry of the bacterium in a non-replicating state while adapting its metabolism to maintain energy levels and a redox balance compatible with survival in the absence of respiration. Accordingly, inhibitors of the regulator which controls the expression of this regulon are actively being sought for their potential to shorten tuberculosis treatment and lower relapse rates when used in combination with standard-of-care antibiotics. Our recent studies indicate that the orthologous regulators of MABSC and MAC play a similar function as in Mtb. Genetic and pharmacological disruption of this regulator in MABSC led to inhibition of biofilm formation in addition to decreasing bacterial viability and reversing drug tolerance under hypoxia. Most importantly, two inhibitors of this regulator in MABSC which we identified showed significant bactericidal activity in MABSC-infected mice in addition to potentiating the activity of standard-of-care antibiotics used in combination. Since these two inhibitors are either clinically-used or in phase II clinical trial, they offer repurposing opportunities that could be a short route to the clinic. These exciting findings stimulated the submission of this grant application in which we propose to thoroughly decipher the mechanisms underlying the therapeutic and adjunct therapeutic benefits of these inhibitors in MABSC (Aim 1) and to determine whether the same therapeutic strategy may be applied to MAC (Aim 2).


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 = $1,203,091 )
2025	2025	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	001	4	6/10/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,203,091
2025	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	3	6/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,203,091

Issue Date FY: 2024 ( Subtotal = $118,512 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	3	8/16/2024	NON-COMPETING CONTINUATION	$118,512
														Subtotal = $118,512

Issue Date FY: 2023 ( Subtotal = $666,325 )
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	001	2	6/1/2023	NON-COMPETING CONTINUATION	$666,325
2023	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	4/20/2023	NEW	$0
														Subtotal = $666,325

Issue Date FY: 2022 ( Subtotal = $645,166 )
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	6/15/2022	NEW	$645,166
														Subtotal = $645,166

Grand Total All Awards = $2,633,094

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Repurposing antimalarials for the treatment of NTM infections

Award Number: R01AI170504

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: 06/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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