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A novel mechanism of rifamycin resistance in Mycobacterium abscessus mediated by a putative helicase

Award Number: R21AI159125
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: 05/20/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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A novel mechanism of rifamycin resistance in Mycobacterium abscessus mediated by a putative helicase - Project Summary: Mycobacterium abscessus (Mab) is a rapidly growing NTM causing skin and soft tissue infections as well as pulmonary infections in patients with chronic lung damage. Mab stands apart as one of the most antibiotic resistant microbial species, making its infections incredibly difficult to treat. Particularly striking is its resistance to rifampicin (RIF), a frontline drug for many mycobacterial infections including tuberculosis. RIF inhibits global RNA synthesis by binding to the b-subunit of bacterial RNA polymerase; additionally it is also known to inhibit replication initiation due to an inhibition of dnaA expression. The intrinsic RIF resistance in Mab has so far been attributed to the presence of an ADP-ribosyltransferase (Arr) activity that ribosylates RIF leading to its inactivation. However, we have recently identified an additional determinant, MAB_3189c - a putative helicase, that confers high levels of RIF resistance in Mab. MAB_3189c expression is RIF inducible and is likely regulated by a RIF-associated element (RAE) dependent transcription factor. In this project we will determine the regulation and function of Mab3189c in RIF resistance. In Aim 1 we will investigate if Mab3189c mediates RIF resistance by either directly protecting RNAP against the action of RIF thereby enabling global RNA synthesis to continue, or by alleviating RIF-sensitive replication initiation at oriM thereby enabling growth in the presence of RIF. In Aim 2 we propose to identify the regulatory protein required for RAE-dependent induction of MAB_3189c. The findings will provide a platform for a long-term study to gain insights into Mab3189c dependent RIF resistance in Mab, and design of new strategies to treat Mab infections.


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 = $0 )
2024	2022	HEALTH RESEARCH, INC.	150 BROADWAY STE 280	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	000	2	3/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $189,135 )
2022	2022	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	2	3/28/2022	NON-COMPETING CONTINUATION	$189,135
														Subtotal = $189,135

Issue Date FY: 2021 ( Subtotal = $226,691 )
2021	2021	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	1	5/20/2021	NEW	$226,691
														Subtotal = $226,691

Grand Total All Awards = $415,826

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A novel mechanism of rifamycin resistance in Mycobacterium abscessus mediated by a putative helicase

Award Number: R21AI159125

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: 05/20/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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