# Transition Metal Homeostasis and Reactive Sulfur Species in Bacterial Pathogens

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $455,318

## Abstract

ABSTRACT
Bacterial infectious disease is a global threat to human health and there is an urgent need to develop new
antimicrobials that limit the impact of life-threatening pathogens. These pathogens include the major causative
agents of nosocomial infections, e.g., Acinetobacter baumannii and Staphylococcus aureus, and a major
respiratory pathogen, Streptococcus pneumoniae. In this renewal application, we seek continuation of our
innovative, strongly integrated and topical research program positioned at an intersection of inorganic chemistry
and microbial physiology, designed to tackle significant gaps in our knowledge in bacterial transition metal
homeostasis (metallostasis) and hydrogen sulfide homeostasis. My group has long-standing interests in the
transcriptional repressor proteins (metallosensors) and metallochaperones that allow a bacterium to respond to
host efforts to restrict transition metal availability or induce metal toxicity. Our subsequent discovery of
transcriptional regulators that “sense” downstream more oxidized forms of hydrogen sulfide, collectively termed
reactive sulfur species (RSS), is foundational to our understanding of hydrogen sulfide signaling via protein
persulfidation (S-sulfuration). Indeed, an emerging consensus holds that the biogenesis of hydrogen sulfide and
RSS provides protection against host weapons reactive oxygen and reactive nitrogen species, and antibiotics,
where they function as antioxidants and signaling molecules. Future research will be carried out in four general
areas: 1) Investigating allostery in transcriptional regulation, where we extend our comprehensive physical
description of metallosensors as dynamically-anchored “allosteric inorganic switches” to RSS sensors, using
state-of-the-art methyl-specific NMR relaxation experiments and a novel mass spectrometry-based kinetic
profiling method used to elucidate the broad principles of RSS specificity in diverse structural classes of
regulators; 2) critically evaluate the RSS signaling hypothesis in A. baumannii, which posits that persulfidation is
a regulatory modification, completely unexplored in bacteria; 3) deduce the global impact of host transition metal
(zinc, iron) starvation (nutritional immunity) using complementary proteomics and metalloproteomics workflows
to define changes in the metalloproteome while identifying metallochaperone targets, in A. baumannii; and 4)
elucidate a poorly understood, infection-relevant iron-catecholate acquisition and detoxification pathway in S.
pneumoniae. Our multidisciplinary approach, which seamlessly spans biophysical, bioinorganic and analytical
chemistries to microbial physiology, will transform our understanding of foundational principles of pathogen
metallostasis and hydrogen sulfide/RSS biogenesis in an effort to discover and characterize new players and
biological processes that can be targeted by novel antibacterial strategies.

## Key facts

- **NIH application ID:** 10168320
- **Project number:** 2R35GM118157-06
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** DAVID P. GIEDROC
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $455,318
- **Award type:** 2
- **Project period:** 2016-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168320

## Citation

> US National Institutes of Health, RePORTER application 10168320, Transition Metal Homeostasis and Reactive Sulfur Species in Bacterial Pathogens (2R35GM118157-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168320. Licensed CC0.

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