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Elucidating repair processes central to fluoroquinolone persistence in growth-inhibited populations

Award Number: F30AI140697
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Elucidating repair processes central to fluoroquinolone persistence in growth-inhibited populations - Project Summary Many antibiotics rapidly kill growing populations of bacteria but struggle to kill non-growing populations. Even for drugs that can kill the majority of growth-inhibited bacteria, such as fluoroquinolones (FQs), the presence of persisters can lead to treatment failure. While current paradigms suggest that persisters survive due to limited antibiotic-induced damage, for FQs this is not the case. In non-growing populations, FQ persisters experience the same amount of antibiotic-induced DNA damage as their genetically identical kin and require the homologous recombination repair machinery during the post-antibiotic recovery period in order to survive. Currently, the mechanism underlying why persisters can survive FQ-induced damage while their clonal kin cannot remains ill-defined. We hypothesize that, i) chromosome number, and ii) the relative timing of DNA synthesis and repair during the post-antibiotic period, are phenotypic variables that govern the likelihood a bacterium will be an FQ persister. Since our first hypothesis is based on the importance of homologous recombination to FQ persistence in growth-inhibited populations, we will use fluorescence-activated cell sorting (FACS) to sort live wild-type and mutant populations of Escherichia coli based on chromosome number as determined by staining with cell-permeant nucleic acid dyes, and will subject the isolated populations to tolerance assays and quantitative PCR for chromosome number verification. To complement these assays, we will use time-lapse microscopy of an FQ-treated E. coli strain that harbors an origin of replication reporter in order to visualize the chromosome content of persisters and nonpersisters during the post-FQ recovery period. Our second hypothesis is based on a recent study from our group that showed that starvation following FQ treatment increased persister levels in non-growing populations in a RecA- and time-dependent manner. To test whether the timing of DNA replication vs. DNA repair during recovery impacts FQ persistence, we will conduct time-lapse fluorescence microscopy of single cells harboring reporters for DNA repair or DNA replication both in the presence and absence of nutrients. We will then conduct bulk culture experiments by employing temperature sensitive mutants and inducible systems of the DNA replication and DNA repair machinery. We will first investigate levofloxacin, a representative FQ, and stationary-phase E. coli cultures, because non-growing infections are the most difficult to eradicate, before establishing the generality of any findings by using other FQs (e.g., moxifloxacin) and bacterial species (e.g., Pseudomonas aeruginosa). Data from these experiments will assess whether chromosome number and the relative timing of DNA synthesis vs. DNA repair during recovery from FQ treatment are phenotypic variables important for FQ persistence. Increased understanding of persister survival tactics will open the door for the development of anti-persister strategies, which would reduce the burden of chronic and relapsing 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: 2024 ( Subtotal = -$42,443 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	6	3/7/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$23,764
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	6	4/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$18,679
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	5	6/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$42,443

Issue Date FY: 2023 ( Subtotal = $36,882 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	002	6	2/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$52,694
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	5	2/15/2023	NON-COMPETING CONTINUATION	$0
2023	2021	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	3	11/23/2022	NON-COMPETING CONTINUATION	-$15,812
														Subtotal = $36,882

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	5	2/16/2022	NON-COMPETING CONTINUATION	$51,036
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	5	5/2/2022	NON-COMPETING CONTINUATION	$717
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	5	5/25/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $59,436 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	003	4	8/12/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$8,400
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	4	7/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,127
2021	2021	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	3	7/23/2021	NON-COMPETING CONTINUATION	-$35,127
2021	2021	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	3	2/24/2021	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $59,436

Issue Date FY: 2020 ( Subtotal = $50,520 )
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	2	2/18/2020	NON-COMPETING CONTINUATION	$50,520
														Subtotal = $50,520

Issue Date FY: 2019 ( Subtotal = $50,016 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	1	2/7/2019	NEW	$50,016
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	1	2/7/2019	NEW	$0
														Subtotal = $50,016

Grand Total All Awards = $206,163

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Elucidating repair processes central to fluoroquinolone persistence in growth-inhibited populations

Award Number: F30AI140697

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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