# Nitrosative Stress and Oral Bacteria

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $361,163

## Abstract

Summary
Nitrite and nitric oxide are widespread and robust signaling modulators that are emerging as
potential new antibacterial therapeutic agents. The oral cavity has particularly high concentrations
of nitrite, which can reach 1mM. Oral microorganisms have adapted to survive such high
nitrosative stress exposure and, we expect, that disruption of these adaptation mechanisms will
reduce growth and survival of bacteria in the oral environment. We know that Porphyromonas
gingivalis, a periodontopathogen, has high tolerance of nitrosative stress. However, the complex
signaling pathways setting the basis of this tolerance are yet to be determined in in this bacterium
as well as in other oral bacteria. Using whole genome expression analysis we have identified hcp
encoding newly re-designated S-nitrosylase as the most dramatically upregulated gene under
nitrosative stress. Furthermore, we demonstrated that regulation of Hcp is dependent on an FNR-
like regulator, HcpR, that employs novel hemin-dependent mechanism to sense nitrosative stress.
We hypothesize that the HcpR-Hcp system is central for adaptation of P. gingivalis to nitrosative
stress. Thus, we will first define the molecular mechanisms of P. gingivalis sensing nitrosative
stress through determination of the structural and biochemical characteristics of HcpR. Since
adaptation to nitrosative stress involves a novel enzymatic activity mediated by Hcp, we will
characterize the Hcp-mediated S-nitrosylome using proteomic approaches. In addition, we will
characterize the mechanism P. gingivalis Hcp employs to mediate protection against nitrosative
stress. Finally, we will investigate the contribution of other putative regulatory and effector
proteins in nitrosative stress defense in P. gingivalis. It is noteworthy, that we will verify the
contribution of the mechanisms under host-pathogen setting. This knowledge will provide the tools
to design agents that can compromise the defense mechanisms of the periodontopathogen and
turn endogenous human host nitrite and nitric oxide into a weapon that inhibits growth of the
bacterium and, ultimately, we can exploit it to treat periodontal disease. We predict that this work
will shed light on nitrosative stress signaling mechanisms in a variety of other bacteria that carry
similar nitrosative stress protection mechanisms to those in P. gingivalis.

## Key facts

- **NIH application ID:** 10440244
- **Project number:** 5R01DE023304-07
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Janina P Lewis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,163
- **Award type:** 5
- **Project period:** 2013-06-26 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440244

## Citation

> US National Institutes of Health, RePORTER application 10440244, Nitrosative Stress and Oral Bacteria (5R01DE023304-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440244. Licensed CC0.

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