# BACTERIAL SECOND MESSENGER MEDIATED VIRULENCE REGULATION IN STREPTOCOCCUS MUTANS

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $31,418

## Abstract

ABSTRACT
Recently a new bacterial second messenger termed cyclic di-adenosine monophosphate(c-di-AMP) has been
identified and shown to play vital roles in diverse bacterial cellular processes. C-di-AMP is essential in many
Gram-positive pathogens including Staphylococcus aureus and Streptococcus pneumoniae. We and others
have found that c-di-AMP is not essential in Streptococcus mutans, an important etiological agent of dental caries
(cavity), but regulates cariogenic biofilm formation, bacterial stress responses, and dynamic polymicrobial
interactions that are crucial for S. mutans fitness and virulence. Little is known about the role of c-di-AMP
signaling pathways that modulate distinct and conserved virulent properties found in S. mutans and other
pathogens. In this proposal, we use S. mutans as a model to elucidate virulence regulation mediated by this
emerging signaling molecule. Inactivation of the gene coding for c-di-AMP producing enzyme reduced bacterial
colonization and virulence in a rat model of dental caries, demonstrating a critical role of c-di-AMP in S. mutans
virulence. Moreover, c-di-AMP-mediated virulence networks are integrated into a key response regulator VicR-
modulated signaling through a newly identified c-di-AMP binding receptor (CabPA). These novel findings led us
to hypothesize that c-di-AMP regulates biofilm formation and other virulence properties via multiple new
pathways, which represent major potential therapeutic targets to develop novel and selective anti-virulence
compounds. Two specific aims are proposed to test the hypothesis: 1) To elucidate c-di-AMP and its receptor
CabPA mediated signaling pathways that modulate the biofilm formation and other virulence properties; 2) To
develop new small molecule compounds that modulate S. mutans virulence by targeting the c-di-AMP producing
enzyme. The proposal would allow us to identify new signaling components and unknown dynamic interactions
in c-di-AMP-mediated pathways responsible for the biofilm formation, oxidative stress, and bacterial
competitiveness, and uncover potential therapeutic targets, which would facilitate the future development of new
small molecule compounds that are amenable for drug discovery. The proposal tests a new hypothesis that links
c-di-AMP signaling to VicR-mediated expression of a variety of virulence genes through a distinct c-di-AMP
receptor, and documents non-essential nature of c-di-AMP signaling in S. mutans, and explores the translational
potential using anti-virulence strategy. Successful completion of this application will have a direct impact on
public health as dental caries and other infectious conditions are widespread due to antibiotic resistance and
lack of effective treatment options. Development of anti-S. mutans virulence strategy in the proposal is also
relevant to devise species-specific anti-virulence strategy targeting significant pathogens such as S. aureus and
S. pneumoniae, which should open a new venue to the desi...

## Key facts

- **NIH application ID:** 9849767
- **Project number:** 5R01DE028329-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Hui Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,418
- **Award type:** 5
- **Project period:** 2019-02-01 → 2020-03-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849767

## Citation

> US National Institutes of Health, RePORTER application 9849767, BACTERIAL SECOND MESSENGER MEDIATED VIRULENCE REGULATION IN STREPTOCOCCUS MUTANS (5R01DE028329-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9849767. Licensed CC0.

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