# Mechanisms of Metal Ion Homeostasis of Oral Streptococci

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $444,868

## Abstract

ABSTRACT
Zinc (Zn) is an essential trace metal to all forms of life that becomes toxic at high concentrations. Because it
has both antimicrobial and anti-inflammatory properties, Zn is used as a therapeutic agent to treat a variety of
infectious and non-infectious human conditions. While the efficacy of Zn as an anticaries agent is somewhat
controversial, Zn salts are used in several oral healthcare products to prevent calculus formation, treat
gingivitis and halitosis, and to control dental plaque accumulation. However, the consequences of rising
salivary Zn levels above physiological concentrations to microbial and host-pathogen interactions are poorly
understood and warrant further investigation. Recently, we discovered that S. mutans, a keystone pathogen in
dental caries, is inherently more tolerant to the toxic effects of Zn than other streptococci, including commensal
species associated with oral health. Using transcriptome and mutational analysis approaches, we identified a
previously uncharacterized P1B-type ATPase exporter and cognate transcriptional factor, which we respectively
named ZccE and ZccR, as primarily responsible for the remarkable high Zn tolerance of S. mutans. Searching
public databases, we found that ZccE is unique to S. mutans providing an opportunity for the development of
Zn-based antimicrobial therapies specifically tailored to eliminate S. mutans. Our working hypotheses are that
the ability to overcome Zn toxicity is an important aspect of S. mutans pathophysiology, and that the
identification of ZccE inhibitors can pave the way for the development of a species-specific Zn-based
therapeutic modality. With the long-term goal of developing new anticaries therapies in mind, the specific goals
of this conceptually, technically, and translationally innovative application are: (i) to uncover the regulatory
mechanisms and pathways that mediate Zn tolerance in S. mutans; (ii) to determine the implications of
increasing Zn concentrations, above physiological levels, to the composition and homeostasis of the oral
microbiome; and (iii) to explore and then develop ZccE as an antimicrobial target. To accomplish these goals,
the PI assembled a multidisciplinary team of investigators with complementary expertise in molecular
microbiology and animal models (Abranches and Lemos), structured-based computer-aided drug design (Li),
and medicinal chemistry (Huigens and Li). Completion of this study will: (i) significantly advance our
understanding of the regulatory mechanisms and pathways that mediate bacterial Zn tolerance with the
potential of revealing new therapeutic targets; (ii) shed light onto the implications and potential of Zn-based
therapies in oral health and, more specifically, in caries control; and (iii) facilitate the rational design of new
antimicrobial therapies to prevent/control the emergence of cariogenic biofilms.

## Key facts

- **NIH application ID:** 10913393
- **Project number:** 5R01DE032555-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Jose A Lemos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $444,868
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913393

## Citation

> US National Institutes of Health, RePORTER application 10913393, Mechanisms of Metal Ion Homeostasis of Oral Streptococci (5R01DE032555-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10913393. Licensed CC0.

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