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A critical role for iron and zinc homeostatic systems in the evolutionary adaptation of Escherichia coli to metal restriction

Paterson, Joy R.; Wadsworth, Joshua M.; Hu, Ping; Sharples, Gary J.

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Authors

Joy Paterson joy.r.paterson@durham.ac.uk
Post Doctoral Research Associate

Josh Wadsworth joshua.m.wadsworth@durham.ac.uk
PGR Student Doctor of Philosophy

Ping Hu



Abstract

Host nutritional immunity utilizes metal deprivation to help prevent microbial infection. To investigate bacterial adaptation to such restrictive conditions, we conducted experimental evolution with two metal sequestering agents. Ethylenediaminetetraacetic acid (EDTA) and diethylenetriamine pentamethylene phosphonic acid (DTPMP) were selected as ligands because they differentially affect cellular levels of iron, manganese and zinc in Escherichia coli. Mutants of E. coli strain BW25113 were isolated after cultivation at sub-minimum inhibitory concentration (MIC) chelant levels and genetic changes potentially responsible for tolerance were identified by whole-genome sequencing. In EDTA-selected strains, mutations in the promoter region of yeiR resulted in elevated gene expression. The yeiR product, a zinc-specific metallochaperone, was confirmed to be primarily responsible for EDTA resistance. Similarly, in two of the DTPMP-selected strains, a promoter mutation increased expression of the fepA-entD operon, which encodes components of the ferric-enterobactin uptake pathway. However, in this case improved DTPMP tolerance was only detectable following overexpression of FepA or EntD in trans. Additional mutations in the cadC gene product, an acid-response regulator, preserved the neutrality of the growth medium by constitutively activating expression of the cadAB regulon. This study uncovers specific resistance mechanisms for zinc and iron starvation that could emerge by selection against host nutritional immunity or competition with heterologous metallophores. It also provides insight into the specific metals affected by these two widely used chelators critical for their antibacterial mode of action.

Citation

Paterson, J. R., Wadsworth, J. M., Hu, P., & Sharples, G. J. (2023). A critical role for iron and zinc homeostatic systems in the evolutionary adaptation of Escherichia coli to metal restriction. Microbial Genomics, 9(12), Article 001153. https://doi.org/10.1099/mgen.0.001153

Journal Article Type Article
Acceptance Date Nov 23, 2023
Online Publication Date Dec 6, 2023
Publication Date Dec 22, 2023
Deposit Date Dec 8, 2023
Publicly Available Date Dec 8, 2023
Journal Microbial Genomics
Publisher Microbiology Society
Peer Reviewed Peer Reviewed
Volume 9
Issue 12
Article Number 001153
DOI https://doi.org/10.1099/mgen.0.001153
Keywords Anti-Bacterial Agents, Zinc, fepA, Edetic Acid, Escherichia coli - genetics, chelating agents, Iron, yeiR, cadC, metal homeostasis, acid tolerance
Public URL https://durham-repository.worktribe.com/output/1985052

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