Abstract
Transition metals serve as an important class of micronutrients that are indispensable for bacterial physiology but are cytotoxic when they are in excess. Bacteria have developed exquisite homeostatic systems to control the uptake, storage, and efflux of each of biological metals and maintain a thermodynamically balanced metal quota. However, whether the pathways that control the homeostasis of different biological metals cross-talk and render cross-resistance or sensitivity in the host-pathogen interface remains largely unknown. Here, we report that zinc (Zn) excess perturbs iron (Fe) and copper (Cu) homeostasis in Escherichia coli, resulting in increased Fe and decreased Cu levels in the cell. Gene expression analysis revealed that Zn excess transiently up-regulates Fe-uptake genes and down-regulates Fe-storage genes and thereby increases the cellular Fe quota. In vitro and in vivo protein-DNA binding assays revealed that the elevated intracellular Fe poisons the primary Cu detoxification transcription regulator CueR, resulting in dysregulation of its target genes copA and cueO and activation of the secondary Cu detoxification system CusSR-cusCFBA Supplementation with the Fe chelator 2,2'-dipyridyl (DIP) or with the reducing agent GSH abolished the induction of cusCFBA during Zn excess. Consistent with the importance of this metal homeostatic network in cell physiology, combined metal treatment, including simultaneously overloading cells with both Zn (0.25 mm) and Cu (0.25 mm) and sequestering Fe with DIP (50 μm), substantially inhibited E. coli growth. These results advance our understanding of bacterial metallobiology and may inform the development of metal-based antimicrobial regimens to manage infectious diseases.
Highlights
Transition metals serve as an important class of micronutrients that are indispensable for bacterial physiology but are cytotoxic when they are in excess
To investigate whether Zn stress perturbs the homeostasis of other transition metals in E. coli, we set out to measure intracellular contents of the physiologically relevant transition metals Zn, Fe, Cu, Mn, and nickel (Ni) in E. coli MG1655 cells cultured to OD6002 of 0.4 under Zn stress
Because macrophages infected with M. tuberculosis were reported to overload up to 0.46 mM Zn to combat the pathogen [14], and previous studies applied 0.1– 0.5 mM Zn to generate moderate to severe Zn stress in various bacterial species [5, 20, 22,23,24], we first chose 0.1 mM Zn, which elicits a moderate Zn stress but did not significantly inhibit the growth of E. coli in our investigations
Summary
Zeling Xu‡, Pengchao Wang‡, Haibo Wang§, Zuo Hang Yu§, X Ho Yu Au-Yeung§, Tasuku Hirayama¶, Hongzhe Sun§, and Aixin Yan‡1 From the ‡School of Biological Sciences and the §Department of Chemistry, University of Hong Kong, Pokfulam Road, Hong Kong, China and the ¶Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, 1-25-4, Dairaku-nishi, Gifu, 501-1196, Japan
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