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The role of purine biosynthesis and stringent response in persistent MRSA endovascular infections

Award Number: R01AI139244
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Staphylococcus aureus is the most common cause of life-threatening endovascular infection, including infective endocarditis (IE) and bacteremia. Despite the use of gold-standard antibiotics, morbidity and mortality associated with these syndromes remain unacceptably high. Emergence of methicillin-resistant S. aureus (MRSA), high rates of vancomycin (VAN) clinical failures, and rising daptomycin (DAP) resistance further emphasize this public health threat. Persistent MRSA bacteremia (PB), defined as ¿ 7 days of positive blood cultures despite appropriate antibiotic therapy, is a very worrisome sub-set of these infections. A particularly problematic metric is that PB strains are deemed “susceptible” in vitro to VAN and DAP by standard CLSI breakpoints, yet, persist in vivo despite appropriate use of these antibiotics. Therefore, PB outcomes present a unique variant of traditional antibiotic “resistance” mechanisms and significant therapeutic challenge to the medical community. Understanding the relevant molecular mechanisms of PB is essential to develop novel strategies to predict and successfully treat PB patients. Our Preliminary Data showed that the PB outcomes are likely to be multifactorial on both phenotypic and genotypic levels. Most interestingly, we have shown the impact of purine biosynthesis and stringent responses on the PB outcomes using both clinical MRSA isolates and laboratory isogenic strain sets. Based on our extensive Preliminary Data, we hypothesize that distinct regulatory cascades activated by purine biosynthesis perturbations and the stringent responses play an important role in the PB outcome. Therefore, in this proposal, we will: i) further define the impact of purine biosynthesis in the PB outcome both phenotypically and genotypically by constructing purF deletion mutations in prototypic clinical PB strains; ii) assess the role of purine biosynthesis in the stringent response as it relates to the PB outcome; iii) determine the relationship between purine biosynthesis and biofilm formation; and iv) validate the role of purine biosynthesis in the PB outcome in vivo in an experimental IE model. These studies will significantly advance our understanding on the mechanisms of persistent MRSA endovascular infection and identify unique signatures for new anti-MRSA agents or strategies to treat clinical infections featuring the PB outcome.


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: 2023 ( Subtotal = $450,790 )
2023	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	12/30/2022	NON-COMPETING CONTINUATION	$450,790
														Subtotal = $450,790

Issue Date FY: 2022 ( Subtotal = $450,790 )
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	12/22/2021	NON-COMPETING CONTINUATION	$450,790
														Subtotal = $450,790

Issue Date FY: 2021 ( Subtotal = $350,807 )
2021	2021	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	11/24/2020	NON-COMPETING CONTINUATION	$350,807
														Subtotal = $350,807

Issue Date FY: 2020 ( Subtotal = $490,169 )
2020	2020	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	12/18/2019	NON-COMPETING CONTINUATION	$490,169
														Subtotal = $490,169

Issue Date FY: 2019 ( Subtotal = $500,831 )
2019	2019	LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG N-14	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	1/11/2019	NEW	$500,831
2019	2019	LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG N-14	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	3/12/2019	NEW	$0
														Subtotal = $500,831

Grand Total All Awards = $2,243,387

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The role of purine biosynthesis and stringent response in persistent MRSA endovascular infections

Award Number: R01AI139244

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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