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Identifying the Molecular Target of Two Novel Compounds Active Against Non-replicating Mycobacterium tuberculosis and Delineating the Role of the Putative Target, InhA, in Non-replicating States

Award Number: K08AI139360
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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Project Summary Candidate and career development plan: Dr. Kohta Saito is an Infectious Diseases physician committed to translational research in the fields of antimicrobial discovery and biology of non-replicating pathogens, specifically Mycobacterium tuberculosis (Mtb). His overarching goal is to become an independent physician- scientist pursuing questions of pathogen stress-response and antibiotic tolerance in order to discover novel treatment methods. In the short term, his goals are: 1. To gain skills in the genetic manipulation of Mtb, 2. To learn lipidomic techniques and apply them to the physiology of pathogen response to drugs and host stress, 3. To hone expertise in the study of immune cell interaction with Mtb, 4. To transition to an independent investigator. Environment: Weill Cornell Medicine (New York, NY) is well suited to develop Dr. Saito's career and already equipped to accomplish the proposed research. A large infectious diseases division, tri-institutional resources, and a collaborative TB Research Unit provide fertile ground for the appropriate training Dr. Saito will undertake. Research: The proposed work extends Dr. Saito's experience with Mtb that become tolerant to antibiotics upon exposure to stresses that cause entry into a non-replicative (NR) state. He will use two compounds that kill NR mycobacteria and identify the NR target. Specifically, he will test whether InhA, a cell wall synthesizing enzyme, is the relevant target. He will also test the essentiality of InhA in NR conditions without compound exposure. Specific Aim 1. Identify the NR target of two novel compounds that kill NR mycobacteria. We hypothesize that two compounds, AN1 and AN2, kill NR Mtb via direct inhibition of InhA. We will test this with 3 methods: 1. Recombineering InhA mutations in Mtb and testing susceptibility to AN1 and AN2 in NR condtions, 2. creating conditional knockdowns of InhA in Mtb and assessing their susceptibility to AN1 and AN2, and 3. comparing lipid profiles of NR Mtb before and after compound exposure. Specific Aim 2. Determine the essentiality of InhA in varied models of NR Mtb. We hypothesize that InhA is essential to Mtb in NR states. We will create a conditional InhA knockout strain, and then assess its viability in relevant stress conditions, including exposure to human macrophages, neutrophils, and serum. Metabolomic and lipidomic changes that occur with knockdown strains in NR conditions will also be investigated. Significance: The proposed work will define a process vital to survival of Mtb in NR states, and delineate the role of InhA in NR states. This will advance the field's understanding of Mtb response to physiologic stresses, and provide drug targets that promise to shorten tuberculosis therapy.


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: 2023 ( Subtotal = $172,006 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	12/6/2022	NON-COMPETING CONTINUATION	$172,006
														Subtotal = $172,006

Issue Date FY: 2022 ( Subtotal = $172,006 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	12/9/2021	NON-COMPETING CONTINUATION	$172,006
														Subtotal = $172,006

Issue Date FY: 2021 ( Subtotal = $172,006 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	12/21/2020	NON-COMPETING CONTINUATION	$172,006
														Subtotal = $172,006

Issue Date FY: 2020 ( Subtotal = $172,006 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	1/8/2020	NON-COMPETING CONTINUATION	$172,006
														Subtotal = $172,006

Issue Date FY: 2019 ( Subtotal = $172,006 )
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	1/23/2019	NEW	$172,006
														Subtotal = $172,006

Grand Total All Awards = $860,030

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Identifying the Molecular Target of Two Novel Compounds Active Against Non-replicating Mycobacterium tuberculosis and Delineating the Role of the Putative Target, InhA, in Non-replicating States

Award Number: K08AI139360

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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