# Role and regulation of intracellular signaling in enterococcal antimicrobial resistance

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $674,564

## Abstract

PROJECT SUMMARY
The continued and inevitable emergence of antibiotic resistance demands a vigorous and sustained
effort to identify fundamentally new targets and strategies for innovative antimicrobial therapeutics.
Antibiotic-resistant enterococci are major causes of hospital-acquired infections. Enterococci are
successful hospital-acquired pathogens in part because of their intrinsic resistance to commonly used
antibiotics that target the bacterial cell envelope, such as cephalosporins. However, many questions
remain regarding the genetic and biochemical basis for cephalosporin resistance in enterococci. Our
preliminary data reveal previously unknown roles for an intracellular nucleotide signal and nucleotide
metabolite in control of enterococcal cephalosporin resistance. Little is known about how the activity
of the enzymes responsible for controlling levels of these intracellular nucleotides is regulated in
response to cell wall stress. Moreover, the targets for the nucleotide signal in enterococci are largely
unknown. Our preliminary data suggest a novel model for regulation in which sensory input from
physical association with other membrane-bound proteins regulates synthesis of the nucleotide signal
in response to cell wall stress. The major knowledge gaps to be addressed are that (i) the
mechanisms by which nucleotide signal synthesis is controlled in enterococci are unknown; (ii) the
molecular target(s) for nucleotide signal in the context of antimicrobial resistance are unknown; and
(iii) the mechanisms by which nucleotide metabolites impact cephalosporin resistance are unknown.
The research proposed here is designed to elucidate new insights into the roles and regulation of
intracellular nucleotides in the biological processes that drive enterococcal cephalosporin resistance.
By doing so, we will provide new insights into the fundamental biological processes that drive key
antibiotic resistance in enterococci and define new targets for innovative therapeutics designed to
impair enterococcal cephalosporin resistance.

## Key facts

- **NIH application ID:** 10879835
- **Project number:** 1R01AI175261-01A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** CHRISTOPHER J KRISTICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $674,564
- **Award type:** 1
- **Project period:** 2024-02-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879835

## Citation

> US National Institutes of Health, RePORTER application 10879835, Role and regulation of intracellular signaling in enterococcal antimicrobial resistance (1R01AI175261-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10879835. Licensed CC0.

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