Wednesday, January 7, 2026 1/7/2026

Design, Syntheses and Studies of Novel Antituberculosis Agents

Award Number: R37AI054193
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Design, Syntheses and Studies of Novel Antituberculosis Agents - Tuberculosis (TB) is a highly contagious airborne pathogen that infects > 2 billion people, of whom an estimated 1.5 million people per year are killed by the disease. The global spread of multi-drug resistant (MDR), extensively-drug resistant (XDR), and totally drug resistant (TDR) strains of tuberculosis emphasizes the great need for new effective treatments. This renewal/Merit Award application capitalizes on the discovery of hits against two critical targets in Mycobacterium tubersuolsis – the imidazo[1,2-a]pyridine-3-carboxamides and the imidazo[2,1-b]pyridine-5- carboxamides that target QcrB and novel scaffolds that target complimentary BD oxidase – and seeks to advance these to potential TB treatments. As the first to patent, prolifically publish, and propose the mechanism of action for the imidazo[1,2-a]pyridine-3-carboxamide (IAPC) series, we are the most experienced group to continue development of this series through primate evaluation in preparation for clinical (human) studies. Additionally, we have disclosed the impressive in vitro properties of imidazo[2,1-b]thiazole 5-carboxamide (IT) series a new promising, rationally designed, scaffold we will continue to develop. This new class has low nanomolar antiTB activity against H37Rv, multidrug resistant (MDR) and extreme drug resistant (XDR) Mtb as well as good in vitro metabolism and in vivo exposure with greater lung to plasma ratios. Most recently, we have discovered a small molecule inhibitor of cytochrome bd oxidase in Mtb. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from the preclinical imidazopyridine (Q203)-induced bacterial death, highlighting the attractiveness of the bd- type terminal oxidase for drug development. Combination of our QcrB and bd oxidase inhibitor is bactericidal against replicating, nutrient-starved and hypoxic antibiotic-tolerant mycobacteria and showed increased efficacy in a mouse model of infection. These results indicate that further complementary development of a compound scaffold inhibiting the cytochrome bd oxidase will enhance the value of a drug combination targeting oxidative phosphorylation for treatment of tuberculosis. Furthermore, all of these heterocyclic scaffolds (IAPC, IT and bd oxidase inhibitor) can be prepared in bulk (50 – 100 g) inexpensively and, from these penultimate intermediates, lead compounds with animal efficacy can be prepared in just one synthetic step (amide bond formation or nucleophilic aromatic substitution) and in multi-gram quantities (>15 g). Through our extensive collaborations, we will evaluate all samples and combinations for antiTB activity. We will also perform related studies, including microbe selectivity, gross toxicity particularly looking to avoid mitochondrial toxicity, metabolism, pharmacokinetics (PK), maximum tolerated dose (MTD), mice and/or monkey efficacy and mode of action studies of any new compounds with promising activity and physicochemical attributes including metabolite identification. Our criteria for a clinical candidate are: selective nanomolar potency against H37Rv and drug resistant Mtb, in vivo efficacy comparable to first line drugs isoniazid and rifampicin (at a dose <100 mg/kg), low toxicity (at least 10x over effective dose), minimal drug-drug interactions, good aqueous solubility (>100 g/mL) and synthetic simplicity/cost effectiveness. A highly qualified team of coworkers and collaborators from experienced laboratories has been assembled to accomplish the overarching goal of providing the TB-research and biomedical communities a promising new anti-tb drug treatment as well as validated new drug targtes (respiratory bc1 complex bd oxidase of Mtb). RELEVANCE (See instructions): Tuberculosis (TB) is a serious global health risk that infects more than 2,000,000,000 people worldwide and causes a death every 20 seconds! The objective of this proposal is to develop cost effective anti-TB agents. The focus


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 = $562,117 )
2025	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	19	8/8/2025	NON-COMPETING CONTINUATION	$562,117
														Subtotal = $562,117

Issue Date FY: 2024 ( Subtotal = $562,125 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	18	7/18/2024	NON-COMPETING CONTINUATION	$562,125
														Subtotal = $562,125

Issue Date FY: 2023 ( Subtotal = $562,443 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	17	7/13/2023	NON-COMPETING CONTINUATION	$562,443
														Subtotal = $562,443

Issue Date FY: 2022 ( Subtotal = $562,712 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	002	16	8/24/2022	NON-COMPETING CONTINUATION	$562,712
2022	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	001	15	4/13/2022	EXTENSION WITH OR WITHOUT FUNDS	$124,555
2022	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	14	4/13/2022	NON-COMPETING CONTINUATION	-$124,555
														Subtotal = $562,712

Issue Date FY: 2021 ( Subtotal = $590,748 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	15	4/26/2021	EXTENSION WITH OR WITHOUT FUNDS	$590,748
														Subtotal = $590,748

Issue Date FY: 2020 ( Subtotal = $466,899 )
2020	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	001	14	8/13/2020	NON-COMPETING CONTINUATION	$466,899
2020	2019	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	13	3/20/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $466,899

Issue Date FY: 2019 ( Subtotal = $466,899 )
2019	2019	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	13	7/31/2019	NON-COMPETING CONTINUATION	$466,899
														Subtotal = $466,899

Issue Date FY: 2018 ( Subtotal = $466,899 )
2018	2018	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	12	8/2/2018	NON-COMPETING CONTINUATION	$466,899
														Subtotal = $466,899

Issue Date FY: 2017 ( Subtotal = $466,899 )
2017	2017	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	11	8/9/2017	NON-COMPETING CONTINUATION	$466,899
														Subtotal = $466,899

Grand Total All Awards = $4,707,741

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Design, Syntheses and Studies of Novel Antituberculosis Agents

Award Number: R37AI054193

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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