# A multiscale approach to develop and apply fluoride efflux inhibitors to reverse oral dysbiosis and eliminate early childhood caries

> **NIH NIH RM1** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $1,157,291

## Abstract

PROJECT SUMMARY/ABSTRACT
The problem: Early childhood caries (ECC) is a lead health problem affecting children. More than half a billion
children worldwide have untreated tooth decay. Pain, impaired nutrition, reduction in school productivity, and
significant costs for care are some of the negative impacts of this disease. The reduced quality of life, morbidity
and even mortality are unacceptable consequences of ECC. Because caries is caused by the metabolism of
dietary sugars by a cariogenic biofilm, it is very difficult to control; the widespread consumption of fermentable
sugars in modern diets favors cariogenic species such as Streptococcus mutans and the opportunistic fungi
Candida albicans in the dental biofilm, perpetuating the caries process. Fluoride is the most effective agent for
caries control, but it has very limited antimicrobial effects because most microbes have membrane proteins to
expel fluoride and keep intracellular concentrations at sub-inhibitory levels. Different oral microbial species
possess different types of fluoride exporters; S. mutans and C. albicans employ CLCF and FEX proteins,
respectively, while beneficial oral streptococci use Fluc proteins. This creates an opportunity to specifically
target pathogenic oral microbes to modify species dynamics towards health-associated symbiotic communities
in biofilms exposed to sugar and fluoride. In this project a team of specialists in structural biology, cariology
and modeling and prediction of microbial systems will develop a new class of anticaries therapy, leveraging the
species-specific susceptibilities to fluoride to create treatments that revert the cariogenic biofilm dysbiosis,
under the same level of fluoride exposure currently available through toothpastes/mouth rinses. This will be
pursued under the following specific aims: S.A.#1: A multiscale approach to develop fluoride efflux inhibitor
treatments for dental pathogens; S.A.#2: A data-driven approach to tailor fluoride-based therapies to patient-
specific oral dysbiosis. Significance: This collaborative effort will develop novel, effective fluoride efflux
inhibitors that potentiate the antimicrobial effects of fluoride ion and inhibit growth of oral pathogens, to treat
oral dysbiosis and eliminate ECC. This study will also establish methods to predict the effect of different
treatments according to the patient's specific oral dysbiosis, so that personalized treatment regimens can be
used to maximize anticaries effects.

## Key facts

- **NIH application ID:** 10990788
- **Project number:** 1RM1DE034220-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Randy B. Stockbridge
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,157,291
- **Award type:** 1
- **Project period:** 2024-09-12 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990788

## Citation

> US National Institutes of Health, RePORTER application 10990788, A multiscale approach to develop and apply fluoride efflux inhibitors to reverse oral dysbiosis and eliminate early childhood caries (1RM1DE034220-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10990788. Licensed CC0.

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