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

> **NIH NIH R01** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2023 · $450,790

## Abstract

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.

## Key facts

- **NIH application ID:** 10543433
- **Project number:** 5R01AI139244-05
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** YAN Q. XIONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $450,790
- **Award type:** 5
- **Project period:** 2019-01-14 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543433

## Citation

> US National Institutes of Health, RePORTER application 10543433, The role of purine biosynthesis and stringent response in persistent MRSA endovascular infections (5R01AI139244-05). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10543433. Licensed CC0.

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