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Coordinate Regulation of Salmonella Virulence and Antimicrobial Resistance by MarR Transcription Factors

Award Number: R01AI150041
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY. MarR (Multiple antibiotic resistance Repressor) proteins comprise an ancient family of transcription factors that are widely conserved in bacteria. In the enteric pathogen Salmonella Typhimurium, MarR is a negative regulator of the AcrAB-TolC drug efflux pump, while another MarR transcription factor called SlyA is a counter-silencer required for the expression of horizontally-acquired virulence genes. We have recently shown that despite its divergent function, SlyA shares with MarR the ability to undergo allosteric modulation by aromatic carboxylate molecules and can influence the mar phenotype by repressing the marRAB operon. Inactivation of TolC, an essential component of the AcrAB and other RND-family efflux pumps, phenocopies a slyA mutation, reducing the expression of Salmonella virulence genes. This suggests that efflux regulates the levels of an endogenous metabolite that interacts with SlyA, which in turn controls MarR expression, completing a regulatory circuit that coordinately links antimicrobial resistance, virulence, and bacterial metabolism. This proposal investigates the hypothesis that Salmonella antimicrobial resistance and virulence are coordinately regulated in response to metabolic signals by the MarR and SlyA transcription factors through the following specific aims: (1) Identification of endogenous ligand(s) that modulate MarR/SlyA activity. Preliminary data indicate that SlyA-interacting ligand(s) are aromatic carboxylates. Specific endogenous ligands will be identified by genetic and metabolomic methods and characterized with regard to affinity and allosteric inhibition. (2) Functional characterization of MarR-SlyA-TolC regulatory interactions in Salmonella antimicrobial resistance and virulence. The contribution of the MarR-SlyA regulatory network to Salmonella phenotypic antimicrobial resistance and virulence will be assessed in vitro and in vivo. (3) Comparative analysis of the MarR and SlyA regulons. MarR/SlyA-regulated genes and binding sites will be comprehensively identified to determine the regulatory requirements for repression and counter-silencing, respectively, and to elucidate the mechanisms of transcriptional network evolution. These studies will provide important insights into a central regulatory network linking bacterial virulence, drug resistance, and metabolism, which can lead to the identification of new therapeutic targets for the prevention or treatment of bacterial 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 = $494,667 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	5	5/13/2024	NON-COMPETING CONTINUATION	$494,667
														Subtotal = $494,667

Issue Date FY: 2023 ( Subtotal = $494,667 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	4	5/25/2023	NON-COMPETING CONTINUATION	$494,667
														Subtotal = $494,667

Issue Date FY: 2022 ( Subtotal = $494,667 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	3	5/18/2022	NON-COMPETING CONTINUATION	$494,667
														Subtotal = $494,667

Issue Date FY: 2021 ( Subtotal = $510,456 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	2	6/1/2021	NON-COMPETING CONTINUATION	$510,456
2021	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	1	5/28/2021	NEW	$0
														Subtotal = $510,456

Issue Date FY: 2020 ( Subtotal = $535,961 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	1	6/22/2020	NEW	$0
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	1	5/29/2020	NEW	$535,961
														Subtotal = $535,961

Grand Total All Awards = $2,530,418

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Coordinate Regulation of Salmonella Virulence and Antimicrobial Resistance by MarR Transcription Factors

Award Number: R01AI150041

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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