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The molecular basis of the carbapenem resistance epidemic

Award Number: R01AI090155
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: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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The molecular basis of the carbapenem resistance epidemic - Summary A common theme in bacterial evolution is how the acquisition of antibiotic resistance can rapidly change the epidemiologic landscape of major human pathogens. Carbapenem Resistant Klebsiella pneumoniae (CRKp), first documented in 1996, is now epidemic in New York City (NYC) hospitals and is reported globally. CRKp infections often result in poor therapeutic indices; thus curbing the incidence of CRKp infections is now a national priority. Currently, three overlapping CRKp epidemics with three different classes of carbapenemases are spreading in different continents. Accelerating these epidemics is the ability of carbapenemase genes, harbored on conjugative plasmids, to spread across the Enterobacteriaceae family. A critical, poorly understood aspect of the CRKp epidemic is the relative contribution of plasmid-mediated transfer and clonal dissemination to driving the regional and global epidemiology. Previously, we used whole genome sequencing (WGS) to dissect the molecular epidemiology and evolution of the main US epidemic CRKp sequence type (ST) 258. Interrogating strains and resistance harboring plasmids within our network of NYC hospitals we found that the majority of ST258 CRKp strains harbor one of three common plasmids carrying a particular class of carbapenemase enzyme, KPC. These data suggest the spread of CRKp is likely the consequence of plasmid-mediated gene transfer and subsequent clonal spread. We therefore hypothesize that this epidemic is primarily due to transmission of resistance harboring plasmids uniquely adapted to specific host genetic backgrounds. In Aim 1, we expand our NYC network to include a large US consortium and to examine the genomic epidemiology of CRKp strains and plasmids across the US. Aim 2 builds on the insights and techniques developed in our previous studies to interrogate the global epidemiology of CRKp via a large clinical isolate collection from over 62 countries, with the goal of constructing a phylogeographic map of strains, plasmids and carbapenemase genes. In this Aim we will also directly test the basis of CRKp strain-plasmid association by comparative transmission efficiency studies of different carbapenemase gene-harboring plasmids into diverse strain backgrounds. Using robust CRKp genomic data obtained in Aims 1 and 2, we will develop a rapid molecular detection assay to identify and track CRKp strains and plasmids in clinical settings. Aim 3 will characterize non-carbapenemase factors that contribute to high-level carbapenemase resistance in CRKp isolates, such as mutations in outer membrane proteins, which result in very poor clinical outcomes. Based on this characterization, some of these highly carbapenemase resistant strains will be selected to build a new, well-curated panel of strains for testing novel antibiotic agents. Taken together, ours is an innovative approach with the potential to make a substantial impact in the field of CRKp epidemiology, develop critically needed diagnostic platforms, and explore efficacy of novel antibiotics against these organisms.


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 = $0 )
2024	2021	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	11	10/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $667,413 )
2021	2021	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	11	11/24/2020	NON-COMPETING CONTINUATION	$667,413
														Subtotal = $667,413

Issue Date FY: 2020 ( Subtotal = $1,114,475 )
2020	2020	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	003	10	5/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$880,208
2020	2020	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	10	12/5/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,114,475
2020	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	9	12/5/2019	NON-COMPETING CONTINUATION	$0
2020	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	002	9	5/6/2020	NON-COMPETING CONTINUATION	-$880,208
														Subtotal = $1,114,475

Issue Date FY: 2019 ( Subtotal = $1,016,803 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	9	11/28/2018	NON-COMPETING CONTINUATION	$1,016,803
														Subtotal = $1,016,803

Issue Date FY: 2018 ( Subtotal = $991,002 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	8	12/12/2017	NON-COMPETING CONTINUATION	$614,820
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	002	8	7/9/2018	NON-COMPETING CONTINUATION	$376,182
2018	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	6	1/12/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $991,002

Issue Date FY: 2017 ( Subtotal = $647,565 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	002	7	5/12/2017	COMPETING CONTINUATION	$0
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	7	12/15/2016	COMPETING CONTINUATION	$647,565
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	003	7	6/8/2017	COMPETING CONTINUATION	$0
2017	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	6	12/12/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $647,565

Issue Date FY: 2015 ( Subtotal = $544,800 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	6	3/30/2015	NON-COMPETING CONTINUATION	$544,800
														Subtotal = $544,800

Issue Date FY: 2014 ( Subtotal = $564,497 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	5	4/17/2014	NON-COMPETING CONTINUATION	$564,497
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	4	2/11/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$22,944
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	3	2/11/2014	NON-COMPETING CONTINUATION	$22,944
														Subtotal = $564,497

Issue Date FY: 2013 ( Subtotal = $838,544 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	3	6/4/2013	NON-COMPETING CONTINUATION	$21,443
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Allergy and Infectious Diseases Research	004	4	9/9/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$334,608
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	3	2/1/2013	NON-COMPETING CONTINUATION	$482,493
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Allergy and Infectious Diseases Research	003	4	8/7/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$450,572
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	005	3	2/11/2014	NON-COMPETING CONTINUATION	$22,944
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Allergy and Infectious Diseases Research	006	4	2/11/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$22,944
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	002	3	8/2/2013	NON-COMPETING CONTINUATION	-$450,572
														Subtotal = $838,544

Issue Date FY: 2012 ( Subtotal = $536,305 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	2/27/2012	NON-COMPETING CONTINUATION	$536,305
														Subtotal = $536,305

Issue Date FY: 2011 ( Subtotal = $237,188 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	3/10/2011	NEW	$237,188
														Subtotal = $237,188

Grand Total All Awards = $7,158,592

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The molecular basis of the carbapenem resistance epidemic

Award Number: R01AI090155

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: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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