# Context-specific modulation of Clostridioides difficile virulence by Vancomycin-resistant Enterococcus faecium

> **NIH NIH R21** · STATE UNIVERSITY OF NY,BINGHAMTON · 2022 · $150,160

## Abstract

Toxin expression and sporulation by Clostridioides difficile are context-specific phenomena that integrate
signals from the surrounding environment including the local nutrient milieu of the intestine. The long-term
goal of this laboratory is to define the mechanistic basis of bacteria-bacteria and host interactions that
modulate virulence of C. difficile. The overall objectives in this proposal are to (i) determine the mechanism
of a diffusible inhibitor of C. difficile growth produced by Vancomycin-resistant Enterococcus faecium
(VRE) and (ii) define the mechanism of a contact-dependent inhibition of C. difficile sporulation by VRE.
The central hypothesis is that VRE modulates C. difficile virulence by multiple context-dependent
mechanisms that vary depending on the available carbon source. The rationale for this project is that
determination of mechanisms of interaction between the two species will allow the development of anti-
VRE treatments that limit the potential for CDI. To attain the overall objectives these two specific aims will
be pursued: Aim 1) Identify the mechanism of carbon source-dependent suppression of C. difficile by VRE.
Based on preliminary data, the working hypothesis is: in the presence of carbon sources that are converted
to organic acids by VRE, C. difficile growth is suppressed below a pH threshold and manipulation of carbon
sources in vitro and in VRE colonized animals will modulate C. difficile virulence. In these experiments a
defined medium will be used to screen a panel of carbon sources, enterococci, lactic acid bacteria and
C.difficile strains to determine conditions modulate growth and these data will be used to develop an
optimized mouse model of VRE-C. difficile infection. Aim 2) Define the contact-dependent interaction with
VRE that inhibits sporulation by C. difficile. Based on preliminary data, the working hypothesis is: in the
absence of a carbon source, VRE inhibits entry into sporulation by C. difficile by a non-diffusible modulator
and inhibition of sporulation in this state will increase the level of toxin produced by C. difficile. In these co-
culture assays and fluorescence microscopy will be used to determine if the suppression of sporulation is
mediated by contact and at what developmental stage sporulation is suppressed. Genetic selection in C.
difficile will be used to determine which component of the sporulation genetic program is affected by VRE.
The research proposed is innovative in the applicant’s opinion because it focuses specifically on
interactions between two gastrointestinal pathogens and how conditions in the gut influence the balance
between virulence traits. The proposed research is significant because it will provide a context for
understanding the potential for C. difficile virulence in VRE-colonized animals, which mirrors the frequent
co-colonization by these two bacteria in human patients.

## Key facts

- **NIH application ID:** 10511292
- **Project number:** 1R21AI171634-01
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** Peter T McKenney
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $150,160
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10511292

## Citation

> US National Institutes of Health, RePORTER application 10511292, Context-specific modulation of Clostridioides difficile virulence by Vancomycin-resistant Enterococcus faecium (1R21AI171634-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10511292. Licensed CC0.

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