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Carbonic anhydrase inhibition as a target for antibiotic synergy in enterococci

Award Number: R03AI168491
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: 11/14/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Carbonic anhydrase inhibition as a target for antibiotic synergy in enterococci - SUMMARY Enterococcus faecalis is a hospital-associated opportunistic pathogen that causes infections with high morbidity and mortality. An increasing occurrence of multidrug-resistant enterococci has driven the need for alternative treatment strategies to combat these pathogens. In this proposal, we describe the isolation and characterization of an unusual gentamicin hypersusceptible E. faecalis strain that was cultured from a patient with infective endocarditis. We performed an in vitro resistance selection with this E. faecalis strain to generate one-step (i.e. single mutation) mutants that displayed wild type gentamicin susceptibility levels. Whole-genome sequencing of the one-step mutants showed that gentamicin hypersusceptibility in the parent strain was caused by a mutation that disrupted the E. faecalis alpha-carbonic anhydrase. Separately, we observed that the carbonic anhydrase inhibitor acetazolamide and gentamicin together displayed synergistic activity at inhibiting the growth of wild type E. faecalis strains. This finding has led us to hypothesize that disruption of carbonic anhydrases can sensitize E. faecalis to killing with aminoglycosides. To determine the mechanistic basis of this synergy, we will examine whether disruption of the E. faecalis alpha-carbonic anhydrase causes increased gentamicin uptake via proton motive force-dependent transport and/or increased membrane permeability (Aim 1). In addition, we will investigate differential synergy between aminoglycosides and chemically diverse carbonic anhydrase inhibitors against isogenic E. faecalis strains expressing different carbonic anhydrase genotypes (Aim 2). This is the first time that a connection between carbonic anhydrase disruption and bacterial membrane energization or permeability will be investigated. Successful completion of this project will increase our understanding of E. faecalis biology, while also providing important pilot data toward the development of a promising new combination therapy for patients with enterococcal infections.


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 )
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	4/17/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2024 ( Subtotal = $79,500 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	2	5/10/2024	NON-COMPETING CONTINUATION	$7,950
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	10/25/2023	NON-COMPETING CONTINUATION	$71,550
														Subtotal = $79,500

Issue Date FY: 2023 ( Subtotal = $79,500 )
2023	2023	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	11/14/2022	NEW	$79,500
														Subtotal = $79,500

Grand Total All Awards = $158,999

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Carbonic anhydrase inhibition as a target for antibiotic synergy in enterococci

Award Number: R03AI168491

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: 11/14/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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