# New understanding of LTA as a determinant of daptomycin susceptibility in VRE E. faecium

> **NIH NIH R21** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $212,500

## Abstract

Project summary:
Enterococci are leading causes of multidrug resistant hospital acquired infection – the first E in
the ESKAPE acronym. Most E. faecium isolates at major centers are vancomycin resistant (VRE),
and daptomycin is often the last line bactericidal drug for treatment. Unfortunately, daptomycin
resistance is increasingly common, and can arise during treatment. Here we discovered a new
vulnerability of VRE that appears to be related to production of membrane anchored lipoteichoic
acid (LTA). A naturally occurring E. faecium mutant in this pathway, isolated from an infected
urinary tract, exhibited hypersusceptibility to daptomycin, with a 20-fold lower MIC to this key drug.
We developed preliminary data to show that this stemmed from a mutation in a gene termed lafB,
which encodes an enzyme that make the immediate precursor glycopeptide onto which LTA is
built. When selecting for revertants to the wild type level of daptomycin susceptibility or greater,
we observed that lafB was always the first to mutate back, indicating that it may be dominant to
other mutations that result in daptomycin resistance. If so, inhibition of lafB would have the
potential to undo daptomycin resistance by other mechanisms, or at minimum, prevent those
mutations from arising during treatment. The following proposal outlines a rigorous set of
experiments to explore this new determinant of daptomycin susceptibility.

## Key facts

- **NIH application ID:** 9926227
- **Project number:** 5R21AI146715-02
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Michael S Gilmore
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $212,500
- **Award type:** 5
- **Project period:** 2019-05-07 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926227

## Citation

> US National Institutes of Health, RePORTER application 9926227, New understanding of LTA as a determinant of daptomycin susceptibility in VRE E. faecium (5R21AI146715-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926227. Licensed CC0.

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