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PLASMID-MEDIATED QUINOLONE RESISTANCE

Award Number: R01AI043312
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: 03/15/1999
PERIOD OF PERFORMANCE END DATE: 03/31/2008

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PLASMID-MEDIATED QUINOLONE RESISTANCE - DESCRIPTION (provided by applicant): Quinolones are widely used antimicrobial agents because of their broad antibacterial spectrum, low toxicity, and reliable action against otherwise resistant pathogens. Bacterial resistance to quinolones, however, is increasing and has reached alarming levels in some parts of Europe and the Far East. Various chromosomal mutations contribute to this resistance. Plasmid-mediated resistance was long thought not to exist. We discovered a plasmid-encoded protein termed Qnr that protects DNA gyrase from quinolone inhibition. Qnr acts additively with chromosomal mechanisms for quinolone resistance, belongs to the pentapeptide repeat family of proteins and, by a gel displacement assay, binds to the gyrase tetramer as well as to the GyrA and GyrB subunits with differing affinities. Although initially found in a limited number of isolates in the United States, the qnr gene has recently been discovered in a larger group of isolates from the Far East. The aims of this proposal are: to elucidate the structural requirements for Qnr binding to gyrase, to establish the gyrase activities that Qnr can protect from quinolone inhibition, to determine whether Qnr can also protect the related quinolone target topoisomerase IV, to explore the hypothesis that Qnr blocks quinolone binding to gyrase, to study Qnr binding quantitatively using surface plasmon resonance, to investigate whether Qnr can also protect gyrase from such protein inhibitors as MccB17, CcdB, and Gyrl, to determine whether Qnr and an active gyrase fragment can co-crystallize for structural analysis by x-ray diffraction, and to study the detailed molecular structure of Qnr plasmids to elucidate how this novel property has been acquired. Qnr prevalence will also be explored utilizing samples from parts of the world where quinolone resistance has become common and also from food animal sources. These studies are important not only for understanding an emerging resistance mechanism but should also reveal details of how DNA gyrase and related topoisomerases function and how proteins in the pentapeptide family interact with and regulate the activity of other proteins.


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: 2007 ( Subtotal = $160,717 )
2007	2007	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	8	4/9/2007	NON-COMPETING CONTINUATION	$160,717
														Subtotal = $160,717

Issue Date FY: 2006 ( Subtotal = $165,517 )
2006	2006	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	7	3/24/2006	NON-COMPETING CONTINUATION	$165,517
														Subtotal = $165,517

Issue Date FY: 2005 ( Subtotal = $169,500 )
2005	2005	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	6	4/1/2005	NON-COMPETING CONTINUATION	$169,500
														Subtotal = $169,500

Issue Date FY: 2004 ( Subtotal = $169,500 )
2004	2004	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	5	5/5/2004	NON-COMPETING CONTINUATION	$169,500
														Subtotal = $169,500

Issue Date FY: 2003 ( Subtotal = $169,500 )
2003	2003	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	4		COMPETING CONTINUATION	$169,500
														Subtotal = $169,500

Issue Date FY: 2001 ( Subtotal = $112,693 )
2001	2001	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	3	2/2/2001	NON-COMPETING CONTINUATION	$112,693
														Subtotal = $112,693

Issue Date FY: 2000 ( Subtotal = $109,442 )
2000	2000	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	2	2/7/2000	NON-COMPETING CONTINUATION	$109,442
														Subtotal = $109,442

Issue Date FY: 1999 ( Subtotal = $121,466 )
1999	1999	LAHEY CLINIC INC	41 MALL ROAD	BURLINGTON	MA	01805	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	1	3/8/1999	NEW	$121,466
														Subtotal = $121,466

Grand Total All Awards = $1,178,335

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PLASMID-MEDIATED QUINOLONE RESISTANCE

Award Number: R01AI043312

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: 03/15/1999

PERIOD OF PERFORMANCE END DATE: 03/31/2008

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