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X-ray Crystallographic Analysis of Diguanylate Cyclase Enzyme-Inhibitor Complexes

Award Number: R03AI101669
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: 06/01/2013
PERIOD OF PERFORMANCE END DATE: 05/31/2015

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X-ray Crystallographic Analysis of Diguanylate Cyclase Enzyme-Inhibitor Complexes - DESCRIPTION (provided by applicant): The long-term goals of this research are to explore the role of c-di-GMP in regulating bacterial signaling and to develop small molecules that interfere with c-di-GMP signaling pathways. C-di-GMP is a bacterial second messenger that commonly regulates biofilm formation in numerous human pathogens, including, among others, Vibrio sp., Salmonella typhimurium, Yersinia pestis, and Pseudomonas aeruginosa. Cellular levels of c-di-GMP are controlled by the opposing activities of diguanylate cyclases that synthesize c-di-GMP and phosphodiesterases that hydrolyze it. C-di-GMP, diguanylate cyclases, and c-di-GMP phosphodiesterases are not found in humans, making c-di-GMP signaling systems an attractive target for anti-bacterial intervention. Here we propose to determine X-ray crystal structures of a diguanylate cyclase in complex with different digualylate cyclase inhibitors. The inhibitors were identified using a high-throughput in vivo genetic screen, demonstrated to specifically inhibit the enzymatic activity of multiple digualylate cyclases from different bacterial species in vitro, and shown to repress biofilm formation under static or flow conditions. The X-ray crystal structures will reveal the mechanistic basis of inhibitor function, e.g. whether the inhibitors are binding to the diguanylate cyclase active site and acting as competitive inhibitors, and also identify the inhibitor functional groups mediating the compound-target interactions. This information will drive structure-activity relationship studies designed t generate tighter binding antagonists through iterative rounds of compound redesign, synthesis, and in vivo genetic and in vitro biochemical analysis.


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: 2017 ( Subtotal = $0 )
2017	2014	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	3	11/4/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $79,500 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	3	5/16/2014	NON-COMPETING CONTINUATION	$79,500
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	1	1/22/2014	NEW	$5,300
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	1/22/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$5,300
														Subtotal = $79,500

Issue Date FY: 2013 ( Subtotal = $79,499 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	1	8/6/2013	NEW	-$79,457
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Allergy and Infectious Diseases Research	003	2	1/22/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$5,300
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	5/10/2013	NEW	$79,458
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Allergy and Infectious Diseases Research	001	2	8/6/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$79,498
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Allergy and Infectious Diseases Research	004	1	1/22/2014	NEW	$5,300
														Subtotal = $79,499

Grand Total All Awards = $158,999

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X-ray Crystallographic Analysis of Diguanylate Cyclase Enzyme-Inhibitor Complexes

Award Number: R03AI101669

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: 06/01/2013

PERIOD OF PERFORMANCE END DATE: 05/31/2015

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