# Role and regulation of peptidoglycan synthases in enterococcal antimicrobial resistance

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $476,642

## 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.
Previous work revealed key roles for two signal transduction systems - the IreK transmembrane
kinase and the CroS/R two-component system - in regulation of cephalosporin resistance, but the
downstream effectors in the signaling pathways that drive cephalosporin resistance remain unknown.
In preliminary studies we showed that two penicillin-binding proteins – enzymes that synthesize
peptidoglycan – are each essential for cephalosporin resistance, yet are functionally distinct from
each other. The mechanisms by which the activity of these penicillin-binding proteins are regulated in
enterococci are unknown, although current models point to the possibility that these penicillin-binding
proteins exist as components of multiprotein peptidoglycan synthase complexes. Our data suggest
that the IreK and CroS/R signaling systems are responsible for regulation of penicillin-binding protein
activity to promote cephalosporin resistance. The major knowledge gaps to be addressed are that (i)
the composition and activity of the peptidoglycan synthases in response to cephalosporin stress are
unknown; (ii) a definitive link between IreK or CroS/R and the peptidoglycan synthases has not been
established; and (iii) the mechanisms by which cephalosporins induce lethality when one
peptidoglycan synthase is impaired is unknown. The research proposed here is designed to elucidate
new insights into the roles and regulation of peptidoglycan synthases 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:** 10124153
- **Project number:** 5R01AI150895-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** CHRISTOPHER J KRISTICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $476,642
- **Award type:** 5
- **Project period:** 2020-03-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124153

## Citation

> US National Institutes of Health, RePORTER application 10124153, Role and regulation of peptidoglycan synthases in enterococcal antimicrobial resistance (5R01AI150895-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10124153. Licensed CC0.

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