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Discovery of novel lead-target pairs and identification of all-oral bactericidal drug regimens for Mycobacterium abscessus lung disease

Award Number: R01AI132374
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Mycobacterium abscessus (Mab) accounts for most pulmonary infections caused by fast-growing non- tuberculous mycobacteria (NTM). Incidence and prevalence rates are increasing throughout the developed world, there is currently no reliable cure for Mab lung disease, and the drug development pipeline is limited to repurposed and largely underperforming antibiotics. During the previous funding cycle, we have leveraged 2 decades of chemical matter, tools and concepts developed by the TB community to build an attractive anti-Mab drug discovery portfolio of 8 novel advanced lead compounds with demonstrated efficacy in an immunocompromised Mab mouse model. Meanwhile, we have optimized an immune-competent model with separately acquired funds to address the caveats of immunodeficiency. We have also uncovered the intrinsic mechanism by which Mab resists rifamycins and used this knowledge to synthesize 20- to 100-fold more potent analogs with 50- to 100-fold improved pharmacokinetic-pharmacodynamic parameters. Using targeted drug combination approaches, we have uncovered outstanding bactericidal synergies between (i) rifabutin, moxifloxacin and tebipenem, and (ii) amoxicillin and each of sulopenem, tebipenem and cefuroxime, all oral - lactams that are approved or in late clinical development, acting synergistically due to the combined inhibition of complementary/redundant peptidoglycan synthesis enzymes. Building on these promising results, the major goals of this renewal application are (i) to advance promising hits and optimize early leads, (ii) to populate the Mab preclinical candidate pipeline and (iii) to identify all-oral bactericidal combination regimens ready to enter clinical trials. Our team of antimycobacterial drug discovery experts in microbiology and pharmacology will continue to leverage the successful partnerships established with external chemistry collaborators. As in the previous funding cycle, we will access compound collections and medicinal chemistry support from academic and Pharma partners, a business model that has proven successful. The hit-to-lead and lead optimization programs will capitalize on our successes with a novel class of non-fluoroquinolone gyrase inhibitors, rifamycin and non-rifamycin RNA polymerase inhibitors, to deliver leads and preclinical development candidates with efficacy in the immuno-compromised and -competent mouse models. To prioritize trial-ready all-oral drug combinations, we will focus our efforts on the bactericidal 2- and 3-drug backbones and combine these with bacteriostatic and bactericidal oral drugs used for the treatment of M. abscessus. Combinations that preserve bactericidal and sterilizing activity of the backbones will be prioritized for testing in both mouse models. Our unique niche consists in a pragmatic approach focused on compound sets active against TB, novel ligand/target pairs and late clinical development candidates or approved antibiotics, maximizing both short and long-term chances of success, to accelerate the discovery of all-oral cures against Mab lung disease.


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: 2024 ( Subtotal = $892,054 )
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	7	7/2/2024	COMPETING CONTINUATION	$0
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	7	6/21/2024	COMPETING CONTINUATION	$804,774
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	7	9/4/2024	COMPETING CONTINUATION	$87,280
														Subtotal = $892,054

Issue Date FY: 2022 ( Subtotal = $906,704 )
2022	2022	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	6	1/20/2022	NON-COMPETING CONTINUATION	$906,704
														Subtotal = $906,704

Issue Date FY: 2021 ( Subtotal = $906,704 )
2021	2021	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	5	1/14/2021	NON-COMPETING CONTINUATION	$906,704
														Subtotal = $906,704

Issue Date FY: 2020 ( Subtotal = $906,704 )
2020	2020	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	4	1/14/2020	NON-COMPETING CONTINUATION	$906,704
														Subtotal = $906,704

Issue Date FY: 2019 ( Subtotal = $859,392 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	002	2	7/19/2019	NON-COMPETING CONTINUATION	-$771,560
2019	2019	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	004	3	9/6/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$40,826
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	1/24/2019	NON-COMPETING CONTINUATION	$771,560
2019	2019	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	3	7/18/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$859,392
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	003	1	9/6/2019	NEW	-$40,826
														Subtotal = $859,392

Issue Date FY: 2018 ( Subtotal = $771,560 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	1/31/2018	NEW	$771,560
														Subtotal = $771,560

Grand Total All Awards = $5,243,118

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Discovery of novel lead-target pairs and identification of all-oral bactericidal drug regimens for Mycobacterium abscessus lung disease

Award Number: R01AI132374

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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