# The Staphylococcus aureus response to nutrient zinc restriction during infection

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $424,580

## Abstract

PROJECT SUMMARY
 Staphylococcus aureus is a significant cause of morbidity and mortality that is increasingly acquiring
resistance to all available antibiotics. One promising area for antimicrobial development involves targeting
bacterial acquisition and utilization of nutrient metal. This strategy exploits the fact that all bacterial
pathogens require nutrient metal to colonize their hosts. In response to this requirement, vertebrates have
evolved powerful defense strategies that sequester nutrient metals from invading pathogens in a process
known as nutritional immunity. One of the most effective metal chelating factors of the immune system is
calprotectin, an abundant protein that sequesters nutrient manganese, iron, and zinc and defends against
microbial infection. In addition to its metal chelating properties, calprotectin is a potent pro-inflammatory
molecule. The individual importance of each of these activities to protection against infection has not been
parsed, and the contribution of calprotectin metal binding to its immunomodulatory properties is not known.
 Prevailing models suggest that nutritional immunity ensures that pathogens are uniformly metal starved
during vertebrate colonization. We have challenged this concept through the application of innovative
imaging technologies, revealing S. aureus is differentially metal starved within abscesses. This discovery
necessitates a reevaluation of the environment encountered by S. aureus during infection, particularly as it
pertains to nutrient metal levels. We have also discovered that the S. aureus response to metal restriction
includes the up-regulation of members of the newly described COG0523 family of zinc metallochaperones.
Our preliminary results reveal that these enzymes enable S. aureus to combat calprotectin-mediated zinc
depletion by delivering zinc to critical metalloproteins involved in genome maintenance.
 Based on these fundamental discoveries, we hypothesize that following colonization of the vertebrate
host, S. aureus encounters immune-mediated metal restriction through the delivery of calprotectin to the site
of infection. In response, S. aureus up-regulates the expression of systems to combat this nutrient limitation.
We envision that this microbial response is heterogeneous, and occurs in a manner dependent on the level
of metal restriction experienced at distinct sites of infection. Finally, we predict that an important aspect of
this response to nutrient limitation is the up-regulation of dedicated metallochaperones that deliver metal to
proteins involved in DNA repair and are required for survival upon exposure to the reactive oxygen burst of
the phagocyte. Experiments in this proposal will test this model by (i) defining the heterogeneous S. aureus
response to metal starvation, (ii) elucidating the mechanism by which calprotectin protects against infection,
and (iii) determining the subcellular fate of metal acquired by S. aureus during metal deprivation. This wo...

## Key facts

- **NIH application ID:** 9943199
- **Project number:** 1R01AI150701-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Eric P Skaar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,580
- **Award type:** 1
- **Project period:** 2020-02-19 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9943199

## Citation

> US National Institutes of Health, RePORTER application 9943199, The Staphylococcus aureus response to nutrient zinc restriction during infection (1R01AI150701-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9943199. Licensed CC0.

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