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Mechanism of action of Dapsone in Mycobacterium leprae

Award Number: R21AI175596
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: 08/25/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Mechanism of action of Dapsone in Mycobacterium leprae - Project Summary Current drug resistance surveillance for leprosy is solely based on the monitoring of clinical symptoms and the molecular identification of specific mutations in known drug resistance genes, which are few and fail to encompass the range of molecular mechanisms responsible for treatment failure. We used comparative genomics of drug-susceptible and drug-resistant Mycobacterium leprae strains to identify novel molecular markers of antibiotic resistance in leprosy. Top candidate genes whose polymorphism potentially associated with drug resistance were characterized using a surrogate Mycobacterium (Mycobacterium tuberculosis) since M. leprae cannot be cultured in vitro. Our preliminary results show that the deletion of one candidate gene in particular, fadD9, in M. tuberculosis significantly enhances dapsone resistance. Analysis of the potential function of this gene combined with the results of an earlier metabolomics study on the effects of antifolates on M. tuberculosis metabolism point to the existence of a previously unknown target of dapsone, independent of the FolP1 enzyme from the folate pathway, the deleterious pharmacological inhibition of which is mitigated by mutations reducing or inhibiting the activity of FadD9. This exploratory project aims to characterize these new mechanisms of susceptibility and resistance to dapsone in mycobacteria. Specifically, we hypothesize that dapsone inhibits the g-aminobutyrate (GABA) aminotransferase, GabT, responsible for the production of succinate semialdehyde (SSA) from GABA, thereby limiting the amount of succinate entering the TCA cycle through the GABA shunt. We further hypothesize that FadD9 converts the product of GabT, SSA, to succinaldehyde and that loss of/reduced function mutations in FadD9 thus prevent the limited amounts of SSA produced by the dapsone-inhibited GabT from being diverted away from the TCA cycle. Aim 1 will use genetic and enzymatic approaches to test the hypothesis that dapsone inhibits GabT. Aim 2 will similarly use a combination of cell-free and whole cell-based approaches to test the hypotheses that (i) FadD9 converts SSA to succinaldehyde and that (ii) clinically-relevant mutations lead to reduced or loss of FadD9 activity. Aim 3 will finally attempt to correlate different levels of dapsone resistance in a collection of well-defined M. leprae isolates to the presence of mutations in folP1, fadD9, and/or potentially gabT, in the same isolates.


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 = $0 )
2025	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	6/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $231,000 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	7/23/2024	NON-COMPETING CONTINUATION	$231,000
														Subtotal = $231,000

Issue Date FY: 2023 ( Subtotal = $191,927 )
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	8/25/2023	NEW	$191,927
														Subtotal = $191,927

Grand Total All Awards = $422,927

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Mechanism of action of Dapsone in Mycobacterium leprae

Award Number: R21AI175596

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: 08/25/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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