# Host-mediated zinc sequestration during Acinetobacter baumannii infection

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $573,287

## 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. One promising potential area of therapeutic development involves targeting
bacterial access to nutrient metal or metal handling. This strategy is based on the fact that all bacterial
pathogens require nutrient metal in order to colonize their hosts, and alterations in dietary metal levels
profoundly affect susceptibility to infection. 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 zinc (Zn) and manganese (Mn). In this application, we describe our use of CP as a probe to
uncover a genetic locus within A. baumannii that is involved in 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), and a D-alanine D-alanine carboxypeptidase that we have named
Zn-regulated lipoprotein A (ZrlA). We have discovered that ZigA is a metallochaperone that provides Zn to
client proteins and is required for the liberation of a biovavailable Zn pool during conditions of Zn starvation.
This finding establishes ZigA as the first example of a Zn metallochaperone in nature. In addition, our model
predicts that ZrlA is required to maintain cell wall architecture during Zn stress. Based on these fundamental
discoveries, we hypothesize that upon Zn starvation, A. baumannii mobilizes Zn to critical Zn-requiring client
proteins, while also activating the expression of a carboxypeptidase involved in peptidoglycan remodeling
that substitutes for the loss of activity of a Zn-requiring paralog. To test this central hypothesis, 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 the pathogenesis of pneumonia.
In these studies, we will (i) define the target of the ZigA Zn-metallochaperone during conditions of CP-
imposed Zn restriction, (ii) elucidate the contribution of ZrlA to peptidoglycan remodeling during conditions
of Zn deprivation, and (iii) determine the importance of Zn distribution during the pathogenesis of A.
baumannii pneumonia. These results will provide fundamental insight into how A. baumannii respond...

## Key facts

- **NIH application ID:** 9854868
- **Project number:** 5R01AI101171-09
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** WALTER J. CHAZIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $573,287
- **Award type:** 5
- **Project period:** 2013-01-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854868

## Citation

> US National Institutes of Health, RePORTER application 9854868, Host-mediated zinc sequestration during Acinetobacter baumannii infection (5R01AI101171-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854868. Licensed CC0.

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