# Host factors required for vancomycin resistance in enterococci

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $234,000

## 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 such as vancomycin-resistant enterococci (VRE) are major causes of
hospital-acquired infections, and there are few good therapeutic options to treat VRE infections. A
great deal is known about the genetic and biochemical mechanisms of vancomycin resistance
provided by the horizontally acquired vanA and vanB gene clusters, which reprogram the native
enterococcal peptidoglycan synthesis pathway to produce and use peptidoglycan precursors
containing D-lactate (instead of the natural D-alanine) at the terminal position of the peptide side
chain. These modified precursors must be acted on by multiple proteins in the native enterococcal
peptidoglycan synthesis pathway to successfully build the essential peptidoglycan, yet the role of
enterococcal host factors in mediating vancomycin resistance is poorly understood. Our data indicate
that host factors encoded in the core enterococcal genome are in fact required for phenotypic
vancomycin resistance conferred by horizontally acquired van gene clusters. In particular, a cell-wall-
stress sensing system known as CroS/R responds to vancomycin-induced cell wall stress in VRE and
drives transcription of host enterococcal genes essential for vancomycin resistance. The first major
knowledge gaps that must be overcome to understand how enterococcal host factors drive
vancomycin resistance, and to subsequently exploit such factors as targets for new therapeutics that
sensitize VRE to vancomycin, are (i) to identify the specific CroS/R-dependent enterococcal host
factors that are required for vancomycin resistance; and (ii) to demonstrate that CroS/R-dependent
host factors are required for vancomycin resistance in all types of clinically relevant VRE. The
research proposed here will fill these gaps to establish a solid foundation for the future development
of new therapeutics that disable vancomycin resistance and potentiate the activity of vancomycin
against VRE.

## Key facts

- **NIH application ID:** 10339472
- **Project number:** 5R21AI153391-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** CHRISTOPHER J KRISTICH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $234,000
- **Award type:** 5
- **Project period:** 2021-02-03 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339472

## Citation

> US National Institutes of Health, RePORTER application 10339472, Host factors required for vancomycin resistance in enterococci (5R21AI153391-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10339472. Licensed CC0.

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