Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/134295
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Type: | Journal article |
Title: | The role of ZntA in Klebsiella pneumoniae zinc homeostasis |
Author: | Maunders, E.A. Ganio, K. Hayes, A.J. Neville, S.L. Davies, M.R. Strugnell, R.A. McDevitt, C.A. Tan, A. |
Citation: | Microbiology Spectrum, 2022; 10(1):e01773-21-1-e01773-21-12 |
Publisher: | American Society for Microbiology |
Issue Date: | 2022 |
ISSN: | 2165-0497 2165-0497 |
Editor: | Yan, A. |
Statement of Responsibility: | Eve A. Maunders, Katherine Ganio, Andrew J. Hayes, Stephanie L. Neville, Mark R. Davies, Richard A. Strugnell, Christopher A. McDevitt, Aimee Tan |
Abstract: | Klebsiella pneumoniae is an opportunistic Gram-negative pathogen that is a leading cause of healthcare-associated infections, including pneumonia, urinary tract infections, and sepsis. Essential to the colonization and infection by K. pneumoniae is the acquisition of nutrients, such as the transition metal ion zinc. Zinc has crucial structural and catalytic roles in the proteome of all organisms. Nevertheless, in excess, it has the potential to mediate significant toxicity by dysregulating the homeostasis of other transition elements, disrupting enzymatic processes, and perturbing metalloprotein cofactor acquisition. Here, we sought to elucidate the zinc detoxification mechanisms of K. pneumoniae, which remain poorly defined. Using the representative K. pneumoniae AJ218 strain, we showed that the P-type ATPase, ZntA, which is upregulated in response to cellular zinc stress, was the primary zinc efflux pathway. Deletion of zntA rendered K. pneumoniae AJ218 highly susceptible to exogenous zinc stress and manifested as an impaired growth phenotype and increased cellular accumulation of the metal. Loss of zntA also increased sensitivity to cadmium stress, indicating a role for this efflux pathway in cadmium resistance. Disruption of zinc homeostasis in the K. pneumoniae AJ218 ΔzntA strain also impacted manganese and iron homeostasis and was associated with increased production of biofilm. Collectively, this work showed the critical role of ZntA in K. pneumoniae zinc tolerance and provided a foundation for further studies on zinc homeostasis and the future development of novel antimicrobials to target this pathway. IMPORTANCE: Klebsiella pneumoniae is a leading cause of healthcare-associated infections, including pneumonia, urinary tract infections, and sepsis. Treatment of K. pneumoniae infections is becoming increasingly challenging due to high levels of antibiotic resistance and the rising prevalence of carbapenem-resistant, extended-spectrum β-lactamases producing strains. Zinc is essential to the colonization and infection by many bacterial pathogens but toxic in excess. This work described the first dissection of the pathways associated with resisting extracellular zinc stress in K. pneumoniae. This study revealed that the P-type ATPase ZntA was highly upregulated in response to exogenous zinc stress and played a major role in maintaining bacterial metal homeostasis. Knowledge of how this major bacterial pathogen resists zinc stress provided a foundation for antimicrobial development studies to target and abrogate their essential function. |
Keywords: | Klebsiella pneumonia; zinc; metal transport; ATPase; zinc homeostasis; ZntA; metal biology |
Rights: | © 2022 Maunders et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
DOI: | 10.1128/spectrum.01773-21 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1122582 http://purl.org/au-research/grants/nhmrc/1180826 http://purl.org/au-research/grants/arc/DP170102102 http://purl.org/au-research/grants/nhmrc/1142695 http://purl.org/au-research/grants/arc/FT170100006 |
Published version: | http://dx.doi.org/10.1128/spectrum.01773-21 |
Appears in Collections: | Medical Sciences publications |
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hdl_134295.pdf | Published version | 2.12 MB | Adobe PDF | View/Open |
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