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The role of NosP in Pseudomonas aeruginosa biofilm development

Award Number: R01GM118894
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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The role of NosP in Pseudomonas aeruginosa biofilm development - Bacterial biofilms are a public health threat because they cause chronic and hospital-acquired infections but are resistant to antibiotics. Failure to characterize the biochemical machinery that drives biofilm dispersal risks missing key targets for treatment of infectious disease. Although nitric oxide (NO)-triggered biofilm dispersal in Pseudomonas aeruginosa (PA), a principal pathogen in cystic fibrosis and hospital-acquired infections, is well documented, the underlying biochemical processes responsible are not understood. To bridge this knowledge gap, a long-term goal of the PI is to determine the mechanism of NO signaling in bacteria and to use this knowledge to develop therapeutic strategies to disperse biofilms. In her previous RO1 funding period, the PI established the NosP (NO sensing protein) family of hemoproteins, which were discovered in her laboratory, as NO sensors that regulate biofilm in many bacteria. Based on studies from the previous funding period, the objective of the proposed work is to characterize the NosP-associated histidine kinase (NahK) and determine the molecular mechanism underlying NO/NosP/NahK regulation of biofilm and virulence in PA. It is hypothesized that NO produced downstream of RsmA binds NosP to trigger biofilm dispersal through NahK and the GacS/Rsm MKN. The GacS/Rsm MKN integrates signals from many sensor kinases to control RsmA, the master regulator of motility/acute infection v. biofilm/chronic infection in PA. The proposal is innovative because it challenges the established GacS/Rsm MKN and forges new logical connections between anaerobic respiration, NO, biofilm, and virulence. This proposal is significant because elucidation of the basis for NO signaling in PA will open new therapeutic opportunities for controlling infection caused by this important human pathogen. The hypothesis will be tested by pursuing three specific aims: (1) to identify NosP/NahK interactions within the GacS/Rsm MKN; (2) to delineate the role of NosP/NahK in modulation of RsmA-controlled phenotypes; and (3) to establish the link between RsmA-regulated denitrification and NosP/NahK signaling. Under aim 1, NahK protein-protein and phosphotransfer interactions with GacS/Rsm MKN members will be characterized as a function of NO/NosP regulation. Under aim 2, the effect of NO/NosP/NahK on virulence, quorum sensing, and cyclic-di-GMP pathways controlled by the RsmA will be quantified. Under aim 3, the effect of NO/NosP/NahK on RsmA-controlled denitrification will be quantified and investigated as a regulatory feedback loop. The PI has significant experience with the proposed assays. Upon completion of these aims, NO/NosP/NahK is expected to be established in controlling the GacS/Rsm motility/virulence switch. This would represent a fundamentally important discovery, defining a new signaling pathway and novel antibiotic targets, for which there is a pressing need, especially considering the increased antibiotic resistance typically seen in biofilming organisms. NO-triggered biofilm dispersal has been widely observed in bacteria, so clinical interventions based on NO signaling have the potential for widespread application, furthering the significance of this project.


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 = $309,848 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	7	3/6/2025	NON-COMPETING CONTINUATION	$309,848
														Subtotal = $309,848

Issue Date FY: 2024 ( Subtotal = $488,566 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	6	2/23/2024	NON-COMPETING CONTINUATION	$309,848
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	6	7/23/2024	NON-COMPETING CONTINUATION	$34,428
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	004	6	9/4/2024	SUPPLEMENT FOR EXPANSION	$144,290
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	005	6	9/23/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	003	5	8/19/2024	COMPETING CONTINUATION	$1,997
2024	2020	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	002	4	8/19/2024	NON-COMPETING CONTINUATION	-$1,997
														Subtotal = $488,566

Issue Date FY: 2023 ( Subtotal = $344,276 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	5	2/24/2023	COMPETING CONTINUATION	$344,276
														Subtotal = $344,276

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	4	1/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $336,496 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	4	3/6/2020	NON-COMPETING CONTINUATION	$33,650
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	4	1/31/2020	NON-COMPETING CONTINUATION	$302,846
														Subtotal = $336,496

Issue Date FY: 2019 ( Subtotal = $336,496 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	3	1/28/2019	NON-COMPETING CONTINUATION	$336,496
														Subtotal = $336,496

Issue Date FY: 2018 ( Subtotal = $433,262 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	2	1/29/2018	NON-COMPETING CONTINUATION	$302,463
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	002	2	8/16/2018	SUPPLEMENT FOR EXPANSION	$97,191
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	2	5/16/2018	NON-COMPETING CONTINUATION	$33,608
														Subtotal = $433,262

Issue Date FY: 2017 ( Subtotal = $325,375 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	1	1/30/2017	NEW	$325,375
														Subtotal = $325,375

Grand Total All Awards = $2,574,319

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The role of NosP in Pseudomonas aeruginosa biofilm development

Award Number: R01GM118894

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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