# The role of manganese homeostasis in the nitric oxide stress response of Salmonella enterica serovar Typhimurium

> **NIH NIH R15** · RHODES COLLEGE · 2022 · $306,869

## Abstract

Summary/Abstract
Nitric oxide (NO·) is a radical molecule produced by cells of the mammalian innate immune
system as a defense against pathogens. While replication of enteric pathogens such as the
Gram-negative bacterium Salmonella is inhibited by NO·, the mechanisms by which NO· exerts
bacteriostatic effects are only partly understood. Salmonella encodes a flavohemoglobin, Hmp,
as a defense against NO· but other pathways and cellular processes are also involved in the
nitric oxide stress response. The goal of this proposal is to characterize the role that the
transition metal ion manganese plays in promoting resistance to, and recovery from, nitrosative
stress in Salmonella. Aim 1 seeks to investigate possible mechanisms underlying the
prolonged period of bacteriostasis observed in manganese-limited Salmonella. Electrode-based
probes and molecular assays will be used to monitor respiratory activity and cellular ATP levels.
This aim will also investigate whether the ability to acquire manganese protects against DNA
damage by determining the frequency of replication blocking-lesions and mutation rates. A role
for manganese-requiring peptidases in promoting turnover of damaged proteins will be studied
using genetic mutants. Aims 2&3 will use growth assays and enzyme activity assays in various
genetic backgrounds. Aim 2 experiments will determine the activities of metalloenzymes that
are putative targets of NO· inhibition and the repair rates of these enzymes following NO·
exposure under manganese-replete and manganese-limited conditions. Aim 3 will investigate
the requirements for efflux of manganese and import of iron and magnesium during late stages
of recovery from nitrosative stress. Aim 4 will use RNA isolation and qPCR to investigate the
expression and activity of alternative manganese-dependent enzymes during the nitrosative
stress response. Characterizing the molecular targets of NO· will improve understanding of how
this innate immune defense molecule exerts its bacteriostatic effects as well as how Salmonella
can circumvent these actions. The long-term objective of this work is to identify novel
candidates for inhibition by future antimicrobial therapies.

## Key facts

- **NIH application ID:** 10514182
- **Project number:** 1R15GM147827-01
- **Recipient organization:** RHODES COLLEGE
- **Principal Investigator:** Elaine R. Frawley
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $306,869
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514182

## Citation

> US National Institutes of Health, RePORTER application 10514182, The role of manganese homeostasis in the nitric oxide stress response of Salmonella enterica serovar Typhimurium (1R15GM147827-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10514182. Licensed CC0.

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