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Elucidating the mechanisms of antibiotic tolerance in Staphylococcus aureus biofilms

Award Number: F32AI169905
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Elucidating the mechanisms of antibiotic tolerance in Staphylococcus aureus biofilms - SUMMARY Staphylococcus aureus is one of the leading causes of bacterial infections in the United States. Invasive S. aureus infections (such as osteomyelitis, endocarditis, and bloodstream infections) are associated with relatively high rates of morbidity and mortality even when treated with appropriate antibiotics. The ability to form biofilms, microbially derived communities where cells grow attached to a surface or as a bacterial conglomerate surrounded by a complex extracellular matrix, has been associated with persistent S. aureus infections. A defining feature of bacterial biofilms, including S. aureus biofilms, is a high tolerance to antibiotics. Despite the clinical significance of the antibiotic tolerance seen in biofilm-mediated infections, the mechanism by which this occurs is poorly understood. Antibiotics have been shown to penetrate S. aureus biofilms, suggesting that there are other mechanisms besides physical occlusion involved in tolerance. One possible explanation for the increase in antibiotic tolerance is an enhanced ability to tolerate oxidative stress, which is seen in biofilm growth. Given the growing body of literature suggesting a role for oxidative stress in antibiotic-mediated killing, we hypothesize that changes in protein production that promote the bacterial oxidative stress response lead to the antibiotic tolerance phenotype seen during biofilm-mediated S. aureus infections. Furthermore, given the important role of the transition metals manganese and iron in S. aureus virulence and the oxidative stress response, we anticipate that the ability to regulate the levels of these metals and their distribution within S. aureus biofilms is integral to the antibiotic tolerance phenotype seen in S. aureus biofilms. In order to test this hypothesis, we will (1) determine the impact of antibiotic exposure on metal regulation and the oxidative stress response in S. aureus biofilms using a combination of fluorescence microscopy along with matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), (2) identify the staphylococcal genes responsible for antibiotic tolerance in biofilm growth using transposon sequencing (TnSeq) and proteomic experiments, and (3) demonstrate the in vivo significance of these findings using an animal model of osteomyelitis, a chronic biofilm-mediated S. aureus infection. The sum of this work will result in not only a better understanding of what the elements are that are responsible for antibiotic tolerance in S. aureus infections, but it will also provide new insight that will be useful in developing therapeutics and treatments aimed at reducing the morbidity and mortality of infections due to S. aureus.


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 = -$15,308 )
2025	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	5/27/2025	NON-COMPETING CONTINUATION	-$15,308
														Subtotal = -$15,308

Issue Date FY: 2023 ( Subtotal = $76,052 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	7/11/2023	NON-COMPETING CONTINUATION	$76,052
														Subtotal = $76,052

Issue Date FY: 2022 ( Subtotal = $71,734 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	1	5/25/2022	NEW	$1,276
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	002	1	5/25/2022	NEW	$0
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	2/1/2022	NEW	$70,458
														Subtotal = $71,734

Grand Total All Awards = $132,478

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Elucidating the mechanisms of antibiotic tolerance in Staphylococcus aureus biofilms

Award Number: F32AI169905

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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