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Alternative Ribosomes & Antibiotic Tolerance in Mycobacteria

Award Number: R01AI132422
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: 06/01/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Alternative Ribosomes & Antibiotic Tolerance in Mycobacteria - Summary Changes in abundance of zinc, an essential nutrient but toxic at high concentrations, necessitates adaptive mechanisms in mycobacteria. Under zinc-rich conditions, mycobacteria synthesize ribosomes with a set of ribosomal (r-) proteins containing the zinc-binding CXXC (C+) motif, while zinc starvation induces paralogs of these proteins called C- (for the lack of CXXC motif) as replacements in the 70S ribosome. Evidence of C+ to C- ribosome remodeling is reported in Mtb from chronic lung infections in mice and humans. Clinical relevance of ribosome remodeling is supported by greater antibiotic resistance in the C- than C+ ribosomes, highlighting the challenges in using ribosome targeting drugs in TB therapy. Previously, we solved the structures of C+ and C- ribosomes to decipher the mechanism of their differential antibiotic resistance. We discovered the C- ribosome as the preferred target of mycobacterial protein Y (Mpy). Mpy is a member of highly conserved family of bacterial protein Y, which binds to the decoding region of the ribosome, thereby hibernating non- translating ribosomes as 70S monosomes in growth arrested cells. The structure identified two distinct drug resistance mechanisms associated with the C- ribosome. Aminoglycoside resistance is largely associated with the preferential binding of Mpy to the decoding center of the C- ribosome, which directly impacts the streptomycin and kanamycin binding pockets within the C- ribosome. Unlike aminoglycosides, tolerance to spectinamides is a direct consequence of the structural changes in the 30S ribosomal subunit due to C+ to C- substitution of the r-protein, S14. During our investigation of ribosome hibernation as a specific response to zinc starvation, we discovered a zinc-sensing Mpy- recruitment factor (Mrf), that ensures Mpy recruitment to C- ribosome. The mechanism by which Mpy is recruited to C- ribosomes, resulting in ribosome hibernation, remains unknown. In this proposal, we will specifically focus on: a) deciphering the mechanism of Mpy recruitment to the ribosome, and b) identifying the mechanistic basis for Mpy-dependent and -independent drug resistance in mycobacteria expressing C- ribosomes. The findings will expand our understanding of antibiotic tolerance associated with ribosome remodeling and hibernation in zinc-starved mycobacteria. Given that lung environment of Mtb in humans is likely zinc-limiting, our findings will inform and improve the therapeutic strategies for TB, possibly leading to a shorter treatment 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 = $446,664 )
2025	2025	HEALTH RESEARCH, INC.	150 BROADWAY STE 280	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	002	8	8/21/2025	NON-COMPETING CONTINUATION	$446,664
2025	2023	HEALTH RESEARCH, INC.	150 BROADWAY STE 280	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	001	6	12/19/2024	COMPETING CONTINUATION	$111,150
2025	2021	HEALTH RESEARCH, INC.	150 BROADWAY STE 280	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	000	5	12/19/2024	NON-COMPETING CONTINUATION	-$111,150
														Subtotal = $446,664

Issue Date FY: 2024 ( Subtotal = $454,818 )
2024	2024	HEALTH RESEARCH, INC.	150 BROADWAY STE 280	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	000	7	7/23/2024	NON-COMPETING CONTINUATION	$454,818
														Subtotal = $454,818

Issue Date FY: 2023 ( Subtotal = $440,628 )
2023	2023	HEALTH RESEARCH, INC.	STE 280, RIVERVIEW CENTER	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	002	6	9/20/2023	COMPETING CONTINUATION	$440,628
2023	2021	HEALTH RESEARCH, INC.	STE 280, RIVERVIEW CENTER	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	000	5	3/29/2023	NON-COMPETING CONTINUATION	$0
2023	2021	HEALTH RESEARCH, INC.	STE 280, RIVERVIEW CENTER	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	001	5	9/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $440,628

Issue Date FY: 2021 ( Subtotal = $405,545 )
2021	2021	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	5	6/24/2021	NON-COMPETING CONTINUATION	$405,545
														Subtotal = $405,545

Issue Date FY: 2020 ( Subtotal = $399,156 )
2020	2020	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	4	5/15/2020	NON-COMPETING CONTINUATION	$399,156
														Subtotal = $399,156

Issue Date FY: 2019 ( Subtotal = $403,825 )
2019	2019	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	3	4/16/2019	NON-COMPETING CONTINUATION	$403,825
														Subtotal = $403,825

Issue Date FY: 2018 ( Subtotal = $400,352 )
2018	2018	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	2	6/1/2018	NON-COMPETING CONTINUATION	$400,352
														Subtotal = $400,352

Issue Date FY: 2017 ( Subtotal = $389,185 )
2017	2017	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	1	5/22/2017	NEW	$389,185
														Subtotal = $389,185

Grand Total All Awards = $3,340,173

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Alternative Ribosomes & Antibiotic Tolerance in Mycobacteria

Award Number: R01AI132422

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: 06/01/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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