# Adaptation of vancomycin-resistant enterococci during bloodstream infection

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $87,870

## Abstract

SUMMARY
The long-term objective of this project is to understand how vancomycin-resistant enterococci (VRE) adapt
during bloodstream infection (BSI) to better tolerate antibiotic and host immune defenses. Enterococci have
evolved over hundreds of millions of years to colonize the gastrointestinal (GI) tract of animals, and they are well
adapted to reside there. VRE causing BSI, however, face substantially different selective pressures, such as
antibiotics in high concentrations, nutrient restriction, and host immune defenses. At our center over the past five
years, patients with VRE-BSIs had a 30-day mortality rate of 36%, which was higher than BSIs due to all other
ESKAPE pathogens. Additionally, VRE-BSIs are often difficult to treat, and nearly one third of patients with VRE-
BSI experience either prolonged bacteremia (≥5 days), or recurrent infection within one year. Here we propose
to study the population-level evolutionary dynamics of VRE sampled from the GI tract and blood of patients with
VRE-BSI, and to characterize bacterial adaptations that promote VRE-BSI. Our central hypothesis is that VRE
isolated from BSIs possess genetic adaptations that enable them to survive in the blood environment. In Aim 1,
we will use bacterial population-level whole genome sequencing to identify genetic adaptations associated with
VRE-BSI. We propose to collect matched samples from VRE GI tract surveillance specimens and VRE-BSI from
approximately 150 patients, and to sequence them deeply to assess the diversity of the VRE population at each
body site. We will also compare VRE-BSI populations collected over time from patients that have persistent or
recurrent VRE-BSI. We will utilize comparative genomics and selection-based analyses to identify bacterial loci
that are candidate targets for selection. In Aim 2, we will quantify the effect of mutations in VRE transcription and
translation genes on antibiotic resistance and tolerance. We have already identified candidate adaptive
mutations in RNA polymerase subunits, ribosomal proteins, a ribosome methyltransferase, and several
transcriptional regulators. We will investigate: 1) The connection between antibiotic exposure and the occurrence
of these mutations in the GI tract and blood of VRE-BSI patients, 2) The effects of these mutations on VRE
transcription and translation, and 3) The contribution of these mutations to resistance and/or tolerance of
antibiotics used to treat VRE-BSI. In Aim 3, we will determine whether mutations in the capsular polysaccharide
(cps) and enterococcal polysaccharide antigen (epa) biosynthetic loci augment VRE growth and survival during
BSI. We will investigate the impact of mutations that alter these cell surface-associated polysaccharides on VRE
survival in whole human blood, in the presence of human neutrophils, as well as in a mouse model of VRE
infection. Overall, this study has the potential to transform our understanding of how antibiotic-resistant bacteria
adapt during hum...

## Key facts

- **NIH application ID:** 11110643
- **Project number:** 3R01AI165519-03S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Daria N Van Tyne
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $87,870
- **Award type:** 3
- **Project period:** 2022-06-03 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11110643

## Citation

> US National Institutes of Health, RePORTER application 11110643, Adaptation of vancomycin-resistant enterococci during bloodstream infection (3R01AI165519-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11110643. Licensed CC0.

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