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Role of ribosome modulating proteins in conferring Mycobacterium abscessus antibiotic resistance

Award Number: R01AI155473
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary: Mycobacterium abscessus (Mab) is a rapidly growing NTM causing skin and soft tissue infections and pulmonary infections in patients with chronic lung damage. It stands apart as one of the most antibiotic resistant microbial species, making its infections incredibly difficult to treat. A combination of an oral macrolide and the aminoglycoside, amikacin, comprises the frontline treatment against Mab. Therapy is prolonged and low cure rates are deplorable. The poor efficacies of these antibiotics result from various mechanisms of intrinsic resistance induced in Mab upon exposure to drugs as well as the host environment. Recently we showed that MabHflX, a conserved ribosome-associated GTPase, is required for macrolide-lincosamide resistance (4). The absence of HflX in a DMs_hflX deletion strain results in an increased population of 70S ribosomes suggesting that HflX is involved in dissociation of ribosomes stalled in the presence of antibiotics. However, the detailed mechanism of HflX-mediated antibiotic resistance, as well as the mechanisms by which antibiotic-bound ribosomal subunits are recycled remain unknown. In another study we demonstrated a role for ARE-ABCF proteins in macrolide/lincosamide resistance. In Aim 1 of this proposal we will use a combination of genetic, biochemical and structural approaches to determine the mechanisms of HflX and ABCF-mediated macrolide-lincosamide resistance. In another independent study, aminoglycoside resistance in zinc-starved M. smegmatis was found to originate from ribosome hibernation, which involves binding of mycobacterial protein Y (MPY). We hypothesize that a low-zinc host environment would similarly result in MPY-dependent ribosome hibernation during Mab infection, and confer resistance to aminoglycosides including amikacin. In Aim 2 of this proposal, we will determine the role of MabMPY in aminoglycoside resistance of which could potentially explain the observed discord between in vitro efficiency and in vivo efficacy of the current treatments (Aim 2). The extreme innate antibiotic resistance of Mab presents a unique opportunity to study the convergence of multiple resistance mechanisms in this pathogen. An in-depth understanding of these various mechanisms is critical in the development of new therapeutic approaches towards treatment of 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: 2023 ( Subtotal = $478,217 )
2023	2023	HEALTH RESEARCH, INC.	STE 280, RIVERVIEW CENTER	MENANDS	NY	12204	ALBANY	USA	Allergy and Infectious Diseases Research	000	4	8/1/2023	NON-COMPETING CONTINUATION	$478,217
														Subtotal = $478,217

Issue Date FY: 2022 ( Subtotal = $475,278 )
2022	2022	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	3	8/16/2022	NON-COMPETING CONTINUATION	$475,278
														Subtotal = $475,278

Issue Date FY: 2021 ( Subtotal = $486,278 )
2021	2021	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	001	2	8/4/2021	NON-COMPETING CONTINUATION	$486,278
2021	2020	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	1	4/6/2021	NEW	$0
														Subtotal = $486,278

Issue Date FY: 2020 ( Subtotal = $500,324 )
2020	2020	HEALTH RESEARCH, INC.	EMPIRE STATE PLAZA	ALBANY	NY	12237	ALBANY	USA	Allergy and Infectious Diseases Research	000	1	9/21/2020	NEW	$500,324
														Subtotal = $500,324

Grand Total All Awards = $1,940,097

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Role of ribosome modulating proteins in conferring Mycobacterium abscessus antibiotic resistance

Award Number: R01AI155473

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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