# Host-mediated zinc sequestration during Acinetobacter baumannii infection

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $728,755

## Abstract

PROJECT SUMMARY
 Acinetobacter baumannii is an important nosocomial pathogen that causes a range of diseases, including
respiratory and urinary tract infections, meningitis, endocarditis, wound infections, and bacteremia. In fact, A.
baumannii is now responsible for up to 20% of all intensive care unit infections in some regions of the world with
pneumonia being the most common presentation. The clinical significance of A. baumannii has been propelled
by this organism’s rapid acquisition of resistance to virtually all antibiotics. The identification of novel targets for
therapeutic intervention is critical to our ability to protect the public health from this emerging infectious threat.
A promising area of therapeutic development exploits the idea that all bacterial pathogens require nutrient metal
to cause infection. This approach mimics host-mediated metal sequestration, which is a potent defense against
infection in a process termed “nutritional immunity”. Paradoxically, dietary restriction of metal exacerbates
infection underscoring how alterations in metal abundance can profoundly impact the outcome of host-pathogen
interactions. The host protein calprotectin (CP) is one of the most important contributors to immune-mediated
metal restriction and CP protects against infection through the chelation of nutrient metals, including zinc (Zn).
 Using CP as a probe, we have uncovered a genetic locus within A. baumannii that is important for survival
during conditions of CP-dependent Zn starvation. This locus encodes a member of the conserved COG0523
family of GTPases that we have named Zur-induced GTPase A (ZigA). We have also found a second COG0523
member within the A. baumannii genome that we refer to as 0934. ZigA and 0934 have biological properties
consistent with metallochaperones that insert Zn into client proteins. Our preliminary data indicate that 0934 and
ZigA bind and regulate client metalloenzymes involved in cell wall synthesis and recycling. Based on these
fundamental discoveries, we hypothesize that A. baumannii colonization of the lung leads to massive
accumulation of CP which starves A. baumannii for nutrient Zn. We further hypothesize that ZigA and 0934
regulate cell wall remodeling during Zn starvation to accommodate insertion of nutrient Zn transporters into the
cell envelope that are necessary to combat host- or dietary-imposed Zn starvation.
 To test this central model, we propose a series of experiments aimed at understanding the mechanism and
pathophysiological consequence of the A. baumannii response to dietary and host-imposed Zn deprivation
during pneumonia. In these studies, we will (i) define the molecular interactions of ZigA and 0934 with their
metalloprotein clients, (ii) interrogate the physiological function of ZigA and 0934 in A. baumannii, and (iii)
determine the importance of ZigA and 0934 in response to Zn starvation during the pathogenesis of pneumonia.
This research will establish a new paradigm for how bacter...

## Key facts

- **NIH application ID:** 10831539
- **Project number:** 5R01AI101171-13
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** WALTER J. CHAZIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $728,755
- **Award type:** 5
- **Project period:** 2013-01-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831539

## Citation

> US National Institutes of Health, RePORTER application 10831539, Host-mediated zinc sequestration during Acinetobacter baumannii infection (5R01AI101171-13). Retrieved via AI Analytics 2026-08-11 from https://api.ai-analytics.org/grant/nih/10831539. Licensed CC0.

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