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A New Paradigm for Beta-lactamase Inhibition Research

Award Number: R21AI123835
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: 06/15/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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A New Paradigm for Beta-lactamase Inhibition Research - The antibiotic resistance problem: Two recent independent studies of the potential economic and social impact have concluded that 300 million people will die prematurely as a result of antimicrobial drug resistance over the next 35 years and that the world can expect to lose between 60 and 100 trillion USD worth of economic output by 2050 if the spread of antimicrobial drug resistance is not brought under control. Resistance to β-lactam antibiotics: β-Lactams remain the single most important antibiotic class. It is estimated that > 50% of all antibiotic prescriptions world-wide are for β-lactam antibiotics (e.g. penicillins, cephalosporins, carbapenems). Carbapenems, the newest and most potent β-lactams, have grown in importance as a first line treatment for the wide range of healthcare-associated infections caused by resistant Gram-negative bacteria. As few alternative treatment options are available, the increase in carbapenem- resistant isolates is a major global public health concern. In these organisms, the major resistance mechanism is production of enzymes called β-lactamases that are able to degrade carbapenems (carbapenemases) in addition to other β-lactams. There two categories of carbapenemases: the metallo β-lactamases (MBLs) that rely on zinc ions for activity and the nucleophilic serine β-lactamases (SBLs). Co-administration of β-lactams and β-lactamase inhibitors is a proven treatment strategy for β-lactamase producers. Unfortunately, the clinically available β-lactamase inhibitors are not very effective against newer SBL-type carbapenemases and are totally ineffective against MBLs. The recent FDA approval of avibactam that has good activity against many SBL-type carbapenemases is encouraging. However, avibactam is not active against MBLs and increasingly bacteria are found to produce both SBLs and MBLs. Project Aims: This proposal aims to identify and develop new β-lactamase inhibitors that function by novel mechanisms that allow them to be inhibitors of both SBLs and MBLs and that may replace, or be combined with, existing agents in new generations of combination therapies effective against multiple classes of carbapenemase. The project is based on new mechanistic arguments concerning previously unrecognized potential chemical behavior of β-lactams. It is hypothesized that strategic placement of certain groups adjacent to the β-lactam C=O bond will create β-lactams that fragment in a unique way when acted upon by either SBL- or MBL-type β-lactamases to create products that are predicted to inhibit these enzymes. The project draws on the skills of three research groups whose expertise spans the areas of medicinal chemistry, biochemistry, structural biology and microbiology in a collaborative research effort to test this new approach to creating dual MBL/SBL inhibiting compounds that have the potential to alleviate the serious unmet medical need created by carbapenemase-producing resistant pathogenic bacteria.


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: 2023 ( Subtotal = $0 )
2023	2020	UNIVERSITY OF WATERLOO	200 UNIVERSITY AVE W	WATERLOO	ON			CAN	Allergy and Infectious Diseases Research	000	2	7/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $190,168 )
2020	2020	UNIVERSITY OF WATERLOO	200 UNIVERSITY AVE W	WATERLOO	ON	N2L 3G1		CAN	Allergy and Infectious Diseases Research	000	2	5/19/2020	NON-COMPETING CONTINUATION	$190,168
														Subtotal = $190,168

Issue Date FY: 2019 ( Subtotal = $110,831 )
2019	2019	UNIVERSITY OF WATERLOO	200 UNIVERSITY AVE W	WATERLOO	ON	N2L 3G1		CAN	Allergy and Infectious Diseases Research	000	1	6/13/2019	NEW	$110,831
														Subtotal = $110,831

Grand Total All Awards = $300,999

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A New Paradigm for Beta-lactamase Inhibition Research

Award Number: R21AI123835

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: 06/15/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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