# Determination of structure-function relationships and role in virulence of a MerR-type regulator that mediates zinc tolerance in Streptococcus mutans

> **NIH NIH F31** · UNIVERSITY OF FLORIDA · 2024 · $44,702

## Abstract

Abstract
Dental caries is the most prevalent chronic infectious disease, with an estimated treatment cost of ~$70
billion/year. While a multifactorial disease, Streptococcus mutans is recognized as a keystone caries pathogen
because of its capacity to modulate the oral biofilm in a way that promotes the establishment of a highly
acidogenic (cariogenic) microbiota. The trace metals iron, manganese, and zinc (Zn) play structural, catalytic,
and regulatory roles in proteins and so are essential to all forms of life. Conversely, these same metals are
toxic when in excess such that the ability to maintain metal homeostasis is a critical aspect of host-pathogen
interactions. The toxicity of Zn derives from its top position in the Irving-Williams series of metal stability, which
allows Zn to avidly bind to non-cognate metalloproteins rendering them nonfunctional. Because it has both
antimicrobial and immunomodulatory properties and relatively low toxicity to mammalian cells, Zn has been
used for decades in medicine, including incorporation into oral health products for the treatment of gingivitis,
halitosis, and prevention of calculus formation. Recently, it was discovered that S. mutans is intrinsically and
substantially more tolerant to toxic levels of Zn than all other streptococci and that this high tolerance is
mediated by a unique P-type ATPase exporter that has been named ZccE. Expression of zccE is controlled by
a unique MerR-type regulator, ZccR for zccE regulator, that strongly activates zccE transcription in response to
high Zn stress. Because both ZccE and ZccR are unique to S. mutans, the Lemos lab proposes that both can
be targeted for the development of a Zn-based therapy tailored against S. mutans. While other projects in the
Lemos lab are exploring the antimicrobial potential of ZccE, the specific aims of this application center around
the ZccR regulator. The goals of this application are to determine the structure-function relationships of ZccR
and explore its potential as an antimicrobial target. To accomplish these goals, the PI will (i) use
crystallography and computational-based approaches to determine the structure of ZccR and identify its critical
functional residues, and (ii) utilize the rat model to determine the contribution of ZccR to oral biofilm
colonization and caries development alone or in combination with topical Zn treatment. Knowledge gained from
this study will facilitate the structure-guided design of small molecule inhibitors for ZccR and reveal the
potential of targeting mechanisms of Zn homeostasis to combat S. mutans infections, with the long-term
objective of developing novel therapies for the prevention of dental caries and treatment of systemic S. mutans
infections (i.e., infective endocarditis). This work will be conducted in a highly supportive and collaborative
research environment with Aim 1 establishing a collaboration between the Lemos and McKenna labs.
Moreover, the comprehensive training plan provided...

## Key facts

- **NIH application ID:** 10895964
- **Project number:** 5F31DE032899-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Alexandra Peterson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,702
- **Award type:** 5
- **Project period:** 2023-08-16 → 2025-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895964

## Citation

> US National Institutes of Health, RePORTER application 10895964, Determination of structure-function relationships and role in virulence of a MerR-type regulator that mediates zinc tolerance in Streptococcus mutans (5F31DE032899-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10895964. Licensed CC0.

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