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The interplay between cell envelope protein homeostasis and antibiotic resistance in Gram-negative bacteria

Award Number: R01AI158753
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: 11/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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The interplay between cell envelope protein homeostasis and antibiotic resistance in Gram-negative bacteria - PROJECT SUMMARY / ABSTRACT Gram-negative bacteria are uniquely equipped to defeat antibiotics. Their outermost layer, the cell envelope, is a natural permeability barrier that contains an array of resistance proteins capable of neutralizing most existing antimicrobials. As a result, its presence creates a major obstacle both for the treatment of resistant infections and the development of new antibiotics. The cell envelope is also home to numerous conserved pathways that safeguard the integrity of its proteome. Despite the central role of these systems in maintaining protein homeostasis, their interaction with resistance proteins localizing in the cell envelope has not been examined. We hypothesized that the activity of cell envelope folding catalysts may be important for the function of resistance determinants, and we tested this hypothesis on a key proteostasis player, the disulfide bond formation system. We discovered that the oxidative-protein-folding activity of this pathway is essential for the function of some of the most epidemiologically relevant and clinically challenging resistance proteins, namely β-lactamases, colistin resistance enzymes, and efflux pumps. Guided by strong preliminary data obtained from model laboratory strains and from clinical isolates, we propose an in- depth investigation of the role of cell envelope proteostasis systems in antibiotic resistance. We will use a combination of bacterial genetics, microbiology, biochemistry, proteomics, experimental evolution, and human disease modeling to pursue three specific aims: 1) Identify the components of the resistome that rely on oxidative protein folding, by assessing the requirement for disulfide bond formation on hundreds of clinically important resistance proteins. 2) Evaluate the impact of oxidative protein folding on resistant infections, by testing our biochemical findings in clinical isolates and in a relevant murine chronic infection model. 3) Explore the role of other cell envelope folding catalysts in antibiotic resistance, by probing their function in multidrug-resistant clinical strains of pathogenic bacteria and validating our results in model laboratory strains. We expect that our holistic approach, spanning multiple resistance determinants and folding catalysts, will break new ground in our understanding of the role of cell envelope proteostasis in resistance. This knowledge will be applicable to many high-priority Gram-negative pathogens and, in the long term, may inspire novel broad-acting strategies for overcoming antibiotic resistance.


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: 2026 ( Subtotal = $389,523 )
2026	2026	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	5	12/4/2025	NON-COMPETING CONTINUATION	$389,523
														Subtotal = $389,523

Issue Date FY: 2025 ( Subtotal = $389,523 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	4	11/6/2024	NON-COMPETING CONTINUATION	$389,523
														Subtotal = $389,523

Issue Date FY: 2024 ( Subtotal = $389,523 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	3	10/24/2023	NON-COMPETING CONTINUATION	$350,570
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	001	3	5/15/2024	NON-COMPETING CONTINUATION	$38,953
														Subtotal = $389,523

Issue Date FY: 2023 ( Subtotal = $389,523 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	2	10/18/2022	NON-COMPETING CONTINUATION	$389,523
														Subtotal = $389,523

Issue Date FY: 2022 ( Subtotal = $389,523 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	1	10/25/2021	NEW	$389,523
														Subtotal = $389,523

Grand Total All Awards = $1,947,615

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The interplay between cell envelope protein homeostasis and antibiotic resistance in Gram-negative bacteria

Award Number: R01AI158753

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: 11/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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