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Understanding B-Lactam Resistance in Acinetobacter baumannii

Award Number: R01AI072219
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: 08/01/2007
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Understanding B-Lactam Resistance in Acinetobacter baumannii - The Centers for Disease Control and Prevention (CDC) designated Carbapenem-Resistant Acinetobacter baumannii (CRAb) an “urgent threat pathogen” for which novel therapies are desperately needed. The current COVID-19 pandemic has only accelerated the emergence of CRAb in medical intensive care units and hospitals, creating a parallel health care crisis in the US. The combination of β-lactamase production and cell penetration challenge every drug class used to treat CRAb. By applying novel chemistry to design more potent “cross-class” boronic acid transition state inhibitors (BATSIs) that are effective β-lactamase inactivators, and developing a deeper understanding of the genetic diversity of β-lactamases present in CRAb, we propose to extend our efforts to also target class B metallo-β-lactamases (MBLs; specifically IMP-1, -14, and NDM-1, as they are the most prevalent MBLs in Ab), and develop drugs that penetrate Ab more readily. We will build upon the efficacy of two potent BATSIs (MB076 and CR167 that were iteratively designed in our current funding cycle) to also interact with Zn2+ ions in the active site of MBLs, as well as penetrate CRAb more effectively. Concurrently, we discovered that OXA β-lactamase overexpression in Ab drives significant collateral changes in bacteria consistent with increased amidase activity. As a result, peptidoglycan integrity is impacted, and new cellular vulnerabilities were revealed. Further studies have also shown that at least five genes become conditionally essential in OXA expressing Ab. As a result, we propose a multidisciplinary approach to overcome CRAb using the following strategies. Firstly, we propose that structural and mechanistic similarities in class B, C, and D β-lactamases can be exploited to permit the design of “cross-class” inhibitors by the addition of novel functional groups (e.g., Zinc Binding groups, ZBGs). In addition, we will design novel cyclic boronates that demonstrate interactions in the active site that inhibit MBLs as well as serine β-lactamases. Secondly, we hypothesize that the penetration of BATSIs into Ab can be improved and overcome by modifications of the R1/R2 side chains to enhance steric and electronic interactions that facilitate passage through porins, specifically CarO. In addition, we will synthesize novel BATSIs that use Fe3+ mediated transport that penetrate CRAb readily and resist efflux. We will perform molecular modeling and structural analyses of CarO to give us insight on how to overcome this major porin conferring imipenem resistance. Studying the mechanistic/structural features inherent to CarO and the imipenem scaffold will facilitate our first two goals. Thirdly, we discovered that OXA β-lactamase expression in CRAb creates new cellular vulnerabilities and that certain gene products become essential for viability, but only in OXA- overexpressing isolates. We propose that these gene products represent novel bacterial targets that can be inhibited by small molecules to selectively kill OXA expressing bacteria. We will use high-throughput screening to identify compounds that selectively kill OXA expressing Ab and identify the cellular target of these inhibitors.


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 = $1,041,584 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	16	8/19/2025	NON-COMPETING CONTINUATION	$520,792
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	15	2/21/2025	COMPETING CONTINUATION	$520,792
2025	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	15	2/21/2025	COMPETING CONTINUATION	$36,189
2025	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	14	2/21/2025	NON-COMPETING CONTINUATION	-$36,189
														Subtotal = $1,041,584

Issue Date FY: 2024 ( Subtotal = $574,870 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	15	5/15/2024	COMPETING CONTINUATION	$521,957
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	15	6/11/2024	COMPETING CONTINUATION	$52,913
2024	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	14	5/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $574,870

Issue Date FY: 2022 ( Subtotal = $384,971 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	14	8/22/2022	NON-COMPETING CONTINUATION	$384,971
														Subtotal = $384,971

Issue Date FY: 2021 ( Subtotal = $385,768 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	13	8/5/2021	NON-COMPETING CONTINUATION	$385,768
														Subtotal = $385,768

Issue Date FY: 2020 ( Subtotal = $386,292 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	12	8/18/2020	NON-COMPETING CONTINUATION	$386,292
2020	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	11	3/28/2020	COMPETING CONTINUATION	$22,668
2020	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	10	3/28/2020	NON-COMPETING CONTINUATION	-$22,668
														Subtotal = $386,292

Issue Date FY: 2019 ( Subtotal = $405,792 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	11	8/30/2019	COMPETING CONTINUATION	$405,792
2019	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	10	8/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,792

Issue Date FY: 2018 ( Subtotal = $322,367 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	10	5/23/2018	NON-COMPETING CONTINUATION	$322,367
														Subtotal = $322,367

Issue Date FY: 2017 ( Subtotal = $322,703 )
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	9	5/19/2017	NON-COMPETING CONTINUATION	$322,703
														Subtotal = $322,703

Issue Date FY: 2016 ( Subtotal = $323,036 )
2016	2016	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	8	5/13/2016	NON-COMPETING CONTINUATION	$323,036
														Subtotal = $323,036

Issue Date FY: 2015 ( Subtotal = $323,370 )
2015	2015	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	7	4/23/2015	NON-COMPETING CONTINUATION	$323,370
														Subtotal = $323,370

Issue Date FY: 2014 ( Subtotal = $360,710 )
2014	2014	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	6	6/6/2014	COMPETING CONTINUATION	$430,602
2014	2014	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	6	7/3/2014	COMPETING CONTINUATION	-$69,892
														Subtotal = $360,710

Issue Date FY: 2011 ( Subtotal = $346,179 )
2011	2011	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	5	7/18/2011	NON-COMPETING CONTINUATION	$346,179
														Subtotal = $346,179

Issue Date FY: 2010 ( Subtotal = $354,727 )
2010	2010	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	4	6/30/2010	NON-COMPETING CONTINUATION	$354,727
														Subtotal = $354,727

Issue Date FY: 2009 ( Subtotal = $372,339 )
2009	2009	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	7/21/2009	NON-COMPETING CONTINUATION	$372,339
														Subtotal = $372,339

Issue Date FY: 2008 ( Subtotal = $367,115 )
2008	2008	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	7/23/2008	NON-COMPETING CONTINUATION	$367,115
														Subtotal = $367,115

Issue Date FY: 2007 ( Subtotal = $367,984 )
2007	2007	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	7/17/2007	NEW	$367,984
														Subtotal = $367,984

Grand Total All Awards = $6,639,807

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Understanding B-Lactam Resistance in Acinetobacter baumannii

Award Number: R01AI072219

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: 08/01/2007

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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