# Periplasmic Zinc Management and Homeostasis in Paracoccus denitrificans

> **NIH NIH R01** · NEW MEXICO STATE UNIVERSITY LAS CRUCES · 2021 · $266,400

## Abstract

ABSTRACT
The prevalence of antibiotic resistance among pathogenic bacteria has become a major health
concern and has spurred the search for novel antibiotic targets. A particularly promising target is
the superfamily of bacterial ATP-binding cassette (ABC) transporters, which couple the hydrolysis
of ATP to the transport of a wide variety of solutes across the cell membrane. Bacterial ABC
transporters work in conjunction with a high affinity solute binding protein (SBP) that specifically
binds substrate and delivers it to the transporter. In Salmonella enterica and Streptococcus
pneumoniae among others, disruption of genes encoding ABC transporters and SBPs specific for
Zn dramatically attenuates virulence in animal models, highlighting these systems as potent drug
targets. We have identified two Zn-specific ABC transporter operons in Paracoccus denitrificans,
ZnuABC and AztABCD, and have characterized a hitherto hypothetical protein (AztD) that acts as
a Zn chaperone, directly transferring Zn to the SBP of that system (AztC). This project will utilize
P. dentrificans as a model for highly homologous systems in human pathogens belonging to the
carbapenem-resistant Enterobacteriacaea (CRE). These organisms are associated with broad-
spectrum antimicrobial resistance and are the causative agents of potentially deadly nosocomial
infections. We will determine the precise mechanism of metal binding and transfer for AztC and
AztD proteins from P. denitrificans and the CRE pathogen Citrobacter koseri using structural and
biophysical techniques. The physiological roles of the Azt and Znu systems will be determined by
making genetic knockouts of these genes in P. denitrficans and characterizing growth deficient
phenotypes in Zn-limited medium. High-resolution structural information combined with in vivo
functionality will yield new insight into the mechanisms of transition metal import in bacteria and
potentially provide a basis for the rational design of metal uptake inhibitors as antibiotics for multi-
drug resistant pathogens. !

## Key facts

- **NIH application ID:** 10078950
- **Project number:** 5R01GM122819-04
- **Recipient organization:** NEW MEXICO STATE UNIVERSITY LAS CRUCES
- **Principal Investigator:** Erik T Yukl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $266,400
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078950

## Citation

> US National Institutes of Health, RePORTER application 10078950, Periplasmic Zinc Management and Homeostasis in Paracoccus denitrificans (5R01GM122819-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10078950. Licensed CC0.

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