# Integration of heme acquisition and signaling in Gram-negative pathogens

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $497,496

## Abstract

PROJECT SUMMARY
ESKAPE pathogens are a leading cause of drug resistant infections and the need to identify new antibacterial
strategies is critical. Iron is an essential micronutrient for survival and virulence that microbial pathogens which
actively sequesters iron away from microorganisms. Pathogens overcome this iron limitation through a variety
of mechanisms, including the synthesis and secretion of siderophores that scavenge ferric (Fe3+) iron, the
uptake of ferrous (Fe2+) iron via Feo or NRAMP-like systems, and acquisition of iron from host heme. iron
acquisition and homeostasis by microbial pathogens is multifactorial and dependent on sophisticated
transcriptional and post-transcriptional regulatory networks. We have recently shown the PhuS cytoplasmic
heme binding protein has a dual function in regulating heme flux through HemO, and in the transcriptional
regulation of the iron and heme regulated sRNA’s PrrF and PrrH. The PrrF sRNAs bind to complementary
sequences of their target RNAs causing the RNAseE and Hfq-dependent mRNA degradation of genes involved
in iron-storage and oxidative stress, aerobic and anaerobic metabolism, including iron containing proteins of
the TCA cycle, as well as several virulence factors. Therefore, regulation of the heme flux through HemO is a
critical link between heme metabolism and the iron-dependent sRNA regulatory network required for
adaptation and virulence within the host. The goal of the proposal is to understand at a molecular level how
heme acquisition is integrated into these regulatory networks. Specifically, we will; i) determine the PhuS
structural motifs required for heme transfer and binding to the prrF1 promoter (PprrF1), ii) define the in vivo
effects of PhuS variants on PrrF/H sRNAs and the downstream regulon. and iii) determine evolutionary
conservation and function of PhuS homologs across enteric pathogens. On completion of the studies we will
have determined the role of extracellular heme metabolism in the iron-dependent regulatory networks of three
significant human pathogens, providing a platform for the identification of antibacterial strategies at the
interface between of iron homeostasis and virulence.

## Key facts

- **NIH application ID:** 10234331
- **Project number:** 1R01AI161294-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Amanda Gail Oglesby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $497,496
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234331

## Citation

> US National Institutes of Health, RePORTER application 10234331, Integration of heme acquisition and signaling in Gram-negative pathogens (1R01AI161294-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10234331. Licensed CC0.

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