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Repurposing Gram-positive Antibiotics for Gram-Negative Bacteria using Antibiotic Adjuvants

Award Number: R01AI167284
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: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Repurposing Gram-positive Antibiotics for Gram-Negative Bacteria using Antibiotic Adjuvants - Multi-drug resistant (MDR) Acinetobacter baumannii infections present an enormous ongoing challenge to public health. Due to the frequent occurrence of multidrug resistance, current treatment options for A. baumannii infections are limited. ß-Lactam antibiotics, especially carbapenems, represent the treatment of choice for susceptible infections. However, carbapenem resistance is increasingly common, and for such infections there is no consensus on the optimal alternative treatment. Because resistance has hitherto been relatively uncommon, colistin has become a favored treatment in spite of the fact that deleterious side effects are common. However, resistance to colistin in A. baumannii is becoming more frequent with the recent dissemination of plasmid-borne colistin resistance genes (mcr-1-10) into healthcare facilities. Unfortunately, the recent track record of discovery of new antibiotics that are active against Gram-negative bacteria is exceedingly poor, which, coupled with the exit of Big Pharma from antibiotic discovery, has made the development of new therapies and non-traditional therapeutic approaches vital. To combat this growing threat, we initiated a research program to identify small molecules, termed antibiotic adjuvants, that potentiate the activity of macrolides against MDR A. baumannii. To this end, we have successfully identified molecules that lower the minimum inhibitory concentration (MIC) of clarithromycin up to 512-fold against all members of a panel of primary clinical A. baumannii isolates from the Walter Reed Army Institute of Research (WRAIR) that encompasses nearly all clinically relevant A. baumannii clades. Adjuvants also potentiate the activity of vancomycin up to 256-fold. Both macrolides and vancomycin are typically viewed as “Gram-positive” selective antibiotics due to their inability to cross the outer membrane of Gram-negative bacteria, Mechanistic studies have led to a working hypothesis that these compounds overcome this barrier by increasing permeability of the outer membrane through inhibiting lipooligosaccharide (LOS) production. Combinations of adjuvant with clarithromycin are effective in a Galleria mellonella model of infection, which has been shown to predict outcome in murine models of infection in the context of MDR A. baumannii. Therefore, combinations of such adjuvants with either clarithromycin or vancomycin may form the basis for an efficacious approach to treating MDR A. baumannii infections for which there are no effective antibiotics.


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 = $1,447,329 )
2025	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	001	4	8/12/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,447,329
2025	2024	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	3	8/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,447,329

Issue Date FY: 2024 ( Subtotal = $734,354 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	3	7/22/2024	NON-COMPETING CONTINUATION	$734,354
														Subtotal = $734,354

Issue Date FY: 2023 ( Subtotal = $739,601 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	2	7/6/2023	NON-COMPETING CONTINUATION	$739,601
														Subtotal = $739,601

Issue Date FY: 2022 ( Subtotal = $769,579 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	1	9/20/2022	NEW	$769,579
														Subtotal = $769,579

Grand Total All Awards = $3,690,863

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Repurposing Gram-positive Antibiotics for Gram-Negative Bacteria using Antibiotic Adjuvants

Award Number: R01AI167284

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: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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