Zinc excess increases cellular demand for iron and decreases tolerance to copper in Escherichia coli
Zinc excess increases cellular demand for iron and decreases tolerance to copper in Escherichia coli
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锌过量会增加细胞对铁的需求并降低大肠杆菌对铜的耐受性
DOI：
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发表时间：
2019
影响因子：
4.8
通讯作者：
A. Yan
中科院分区：
文献类型：
--
作者：
Zeling Xu;Pengchao Wang;Haibo Wang;Zuo Hang Yu;H. Au;T. Hirayama;Hongzhe Sun;A. Yan
过渡金属是一类重要的微量营养素，对于细菌生理学是必不可少的，但过量时会产生细胞毒性。细菌已经发展出精致的稳态系统来控制每种生物金属的吸收、储存和流出，并维持热力学平衡的金属配额。然而，控制不同生物金属稳态的途径是否会相互干扰并在宿主-病原体界面中产生交叉耐药性或敏感性仍然很大程度上未知。在此，我们报告过量的锌 (Zn) 会扰乱大肠杆菌中的铁 (Fe) 和铜 (Cu) 稳态，导致细胞内铁 (Fe) 水平增加和铜 (Cu) 水平下降。基因表达分析表明，锌过量会短暂上调铁吸收基因并下调铁储存基因，从而增加细胞铁配额。体外和体内蛋白质-DNA结合测定表明，细胞内Fe升高会毒害初级铜解毒转录调节因子CueR，导致其靶基因copA和cueO失调，并激活次级铜解毒系统CusSR-cusCFBA。补充 Fe 螯合剂 2,2'-联吡啶 (DIP) 或还原剂 GSH 消除了 Zn 过量时 cusCFBA 的诱导。与这种金属稳态网络在细胞生理学中的重要性相一致，联合金属处理，包括同时用 Zn (0.25 mm) 和 Cu (0.25 mm) 使细胞超载，以及用 DIP (50 μm) 螯合 Fe，显着抑制了大肠杆菌的生长。这些结果增进了我们对细菌金属生物学的理解，并可能为开发基于金属的抗菌疗法来控制传染病提供信息。
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.
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DOI：
10.1016/s0021-9258(19)69880-7
发表时间：
1981-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
S. Boylan;E. E. Dekker-E.
通讯作者：
S. Boylan;E. E. Dekker-E.
DOI：
10.1073/pnas.97.2.652
发表时间：
2000-01-18
影响因子：
11.1
作者：
Rensing, C;Fan, B;Rosen, BP
通讯作者：
Rosen, BP
影响因子：
2.1
作者：
Gudipaty SA;Larsen AS;Rensing C;McEvoy MM
通讯作者：
McEvoy MM
影响因子：
10.5
作者：
ELLEDGE, SJ;DAVIS, RW
通讯作者：
DAVIS, RW
影响因子：
7.8
作者：
Braymer, Joseph J.;Giedroc, David P.
通讯作者：
Giedroc, David P.