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Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb.

Award Number: U19AI142735
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The main objective of the CETR is to modulate protein production and degradation as an integrated approach to rapid sterilization of drug sensitive (DS) and drug resistant tuberculosis (DR-TB) with the ultimate goal of delivering 2 investigational new drug (IND) applications and a regimen that will be effective against both DS and DR-TB and could result in relapse-free cures of TB-infected mice in 2 months or less, while also suppressing resistance development. Historically, TB treatment regimen development has been largely empiric. Our current treatment arises from serial clinical trials performed over the course of decades. Recently, we have accelerated this empiric process using a mouse model which, thus far, has excellent predictive power. However, any rationale for these regimens is ex post facto - we really do not understand why certain combinations are better than others. Here we will endeavor to devise a better regimen from first principles. We know that inhibition of RNA polymerase (RNAP) is clinically proven to shorten therapy dramatically and that rifampin synergizes with a variety of drugs. Using genetic studies, we have found that protein degradation is a particularly vulnerable process as even modest inhibition of Clp protease activity results in cell death. We reason that multiple insults in the “proteostasis” pathway that leads from transcription through translation and protein turnover will likely result in more potent TB treatment regimens. Indeed, our preliminary in vivo data suggest this is true. This multidisciplinary CETR consortium will bring together key expertise on three major drug targets that constitute the complex and coordinated network of processes that maintain proteostasis in TB. Through this highly interconnected set of projects and cores we will be able to: Identify modulators of the Clp protease complex by discovering an orally active modulator of ClpC1, and a small molecule ClpP1P2 protease inhibitor (Project 1 and Project 2 and Cores A, B and C). Using structure guided drug discovery approaches and the latest formulation technologies these modulators will be optimized and advanced to preclinical candidate selection. We expect at least one preclinical candidate to emerge from these various approaches. Identify novel RNAP inhibitors that bind and inhibit the enzyme at a non-overlapping site than rifamycins that will therefore be effective against both drug-sensitive and DR-TB (Project 3 and Cores A, B, and C). Use of structural information and computational chemistry will guide our effort to preclinical candidate selection. Using an in vitro hollow fiber system and mouse Mtb-infection models, we will characterize the PK/PD relationships that govern the anti-TB activity and suppression of drug-resistant mutants for each drug candidate (ClpC1 modulators [Project 1], ClpP1P2 modulators [Project 2], RNAP inhibitors [Project 3] and a safer oxazolidinone already identified and currently in IND enabling studies, [Project 4]) and deliver the optimal universally active regimen.


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 = -$3 )
2025	2023	THE GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT INC	80 PINE ST FL 20	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	11/26/2024	NON-COMPETING CONTINUATION	-$3
														Subtotal = -$3

Issue Date FY: 2023 ( Subtotal = $5,472,466 )
2023	2023	THE GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT INC	40 WALL ST	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	001	5	3/24/2023	NON-COMPETING CONTINUATION	$0
2023	2023	THE GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT INC	40 WALL ST	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	3/13/2023	NON-COMPETING CONTINUATION	$5,472,466
														Subtotal = $5,472,466

Issue Date FY: 2022 ( Subtotal = $5,956,416 )
2022	2022	GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT, INC., THE	40 WALL ST FL 24	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	3/22/2022	NON-COMPETING CONTINUATION	$5,956,416
														Subtotal = $5,956,416

Issue Date FY: 2021 ( Subtotal = $6,025,401 )
2021	2021	GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT, INC., THE	40 WALL ST FL 24	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	4/8/2021	NON-COMPETING CONTINUATION	$6,025,401
														Subtotal = $6,025,401

Issue Date FY: 2020 ( Subtotal = $5,528,394 )
2020	2020	GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT, INC., THE	40 WALL ST FL 24	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	001	2	8/28/2020	NON-COMPETING CONTINUATION	$0
2020	2020	GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT, INC., THE	40 WALL ST FL 24	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	3/31/2020	NON-COMPETING CONTINUATION	$5,528,394
														Subtotal = $5,528,394

Issue Date FY: 2019 ( Subtotal = $5,485,460 )
2019	2019	GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT, INC., THE	40 WALL ST FL 24	NEW YORK	NY	10005	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	4/1/2019	NEW	$5,485,460
														Subtotal = $5,485,460

Grand Total All Awards = $28,468,134

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Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb.

Award Number: U19AI142735

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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