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Diagnosing reactive oxygen species in bacteria

Award Number: R01GM141252
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Diagnosing reactive oxygen species in bacteria - Bacteriologists have proposed that numerous stresses are toxic to bacteria because they stimulate the intracellular production of superoxide and hydrogen peroxide. In most cases, no molecular mechanism has been determined, and none is self-evident. Many of these proposals are based upon data from redox-active fluorescent dyes, which are believed to detect intracellular reactive oxygen species (ROS). However, those results have not always been supported by other more-direct methods. This proposal includes preliminary evidence that highlights two concerns about these dyes: that they can be oxidized by intracellular species other than ROS, and that the amount of dye that loads into cells can be affected by stress. Aim 1 will systematically test the utility of fluorescein dyes, which are oxidized by hydroxyl radicals, and ethidine dyes, which react with superoxide. Signals will be quantified in E. coli strains in which ROS are adjusted over the range of biological relevance. Dye signals will be normalized to their intracellular concentrations, using a novel technique. The result will be a rigorous test of their validity as ROS sensors. Aim 2 will develop an alternative marker of oxidative stress that is expected to be reliable, relevant, and accessible to non-experts. Serine dehydratase is a widely distributed enzyme whose iron-sulfur cluster is converted by oxidants to a unique [3Fe-4S] form that can be diagnosed through simple in vitro methods. This Aim will optimize these measurements and test whether the enzyme responds to the levels of ROS that are pertinent in vivo. Aim 3 will then investigate two antibiotics whose toxic actions have been proposed to depend upon intracellular ROS. Streptonigrin is thought to generate toxic amounts of H2O2 through redox- cycling, with the H2O2 then reacting with drug-bound Fe(II) to produce fatal hydroxyl radicals. However, an alternative model considered here suggests that redox-cycling may be minimal and free H2O2 may not participate. Experiments will distinguish between these two hypotheses. Trimethoprim is an inhibitor of thymine synthesis, and published data indicates that H2O2 can contribute to its lethality. Authors conjectured that thymine-starved cells produce toxic amounts of H2O2. A different possibility is that exogenous H2O2 creates DNA damage that thymineless cells struggle to repair. These two sub- aims introduce several distinct ways in which ROS may drive the action of antibiotics. These concepts and experimental approaches can guide the analysis of lead compounds whose antibiotic actions are suspected of involving ROS.


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 = -$1,012 )
2026	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	4	12/2/2025	NON-COMPETING CONTINUATION	-$1,012
														Subtotal = -$1,012

Issue Date FY: 2024 ( Subtotal = $305,434 )
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	001	4	7/25/2024	NON-COMPETING CONTINUATION	$30,543
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	4	3/19/2024	NON-COMPETING CONTINUATION	$274,891
														Subtotal = $305,434

Issue Date FY: 2023 ( Subtotal = $305,434 )
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	3	3/10/2023	NON-COMPETING CONTINUATION	$305,434
														Subtotal = $305,434

Issue Date FY: 2022 ( Subtotal = $305,434 )
2022	2022	UNIVERSITY OF ILLINOIS	352 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	2	3/16/2022	NON-COMPETING CONTINUATION	$274,890
2022	2022	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	001	2	6/21/2022	NON-COMPETING CONTINUATION	$30,544
														Subtotal = $305,434

Issue Date FY: 2021 ( Subtotal = $305,434 )
2021	2021	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	1	3/24/2021	NEW	$305,434
														Subtotal = $305,434

Grand Total All Awards = $1,220,724

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Diagnosing reactive oxygen species in bacteria

Award Number: R01GM141252

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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