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Metal homeostasis and resistance in bacteria

A Corrigendum to this article was published on 12 May 2017

This article has been updated

Key Points

  • Specific protein-based and riboswitch-based metal sensors monitor the intracellular levels of metal ions and regulate the expression of pathways for uptake, storage and efflux, as well as alternative enzymes that use a different metal or non-metal cofactor.

  • Transcription factors often mediate graded responses in which different genes are regulated at different levels of signal.

  • Metal ions are required for growth, with cellular concentrations of Zn(II), Mn(II) and Fe between 0.4–1 mM under sufficient conditions.

  • Metals are present in metalloenzymes, which are stored in membrane or protein compartments, and are present in a low-molecular-weight labile pool.

  • Inhibition of bacterial growth due to metal limitation often occurs as a result of the failure of metal-dependent enzymes.

  • Inhibition of bacterial growth due to metal intoxication can involve the production of harmful reactive oxygen species and/or the incorrect metallation of enzymes that are involved in key metabolic pathways.

  • The host immune system has evolved to take advantage of both metal limitation ('nutritional immunity') and metal intoxication as methods of responding to infection.

  • Metal limitation and intoxication are evolutionarily conserved mechanisms that are used by protozoa and higher eukaryotes to kill bacteria.


Metal ions are essential for many reactions, but excess metals can be toxic. In bacteria, metal limitation activates pathways that are involved in the import and mobilization of metals, whereas excess metals induce efflux and storage. In this Review, we highlight recent insights into metal homeostasis, including protein-based and RNA-based sensors that interact directly with metals or metal-containing cofactors. The resulting transcriptional response to metal stress takes place in a stepwise manner and is reinforced by post-transcriptional regulatory systems. Metal limitation and intoxication by the host are evolutionarily ancient strategies for limiting bacterial growth. The details of the resulting growth restriction are beginning to be understood and seem to be organism-specific.

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Figure 1: Types of metalloregulatory systems.
Figure 2: Metalloregulation in Bacillus subtilis as a model system.
Figure 3: Mechanisms of stepwise regulation of the Zur regulon.

Change history

  • 12 May 2017

    The acknowledgement section has been modified to include funding for Christopher Rensing. The following text has been added: C.R. is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (grants XDB15020402 and XDB15020302) and the 100 Talent Program of Fujian Province China.


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Work in the author's laboratory was funded by a grant from the US National Institutes of Health (grant GM059323 to J.D.H). C.R. is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (grants XDB15020402 and XDB15020302) and the 100 Talent Program of Fujian Province China.

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PowerPoint slides


Iron–sulfur clusters

Enzyme cofactors that are composed of iron coordinated by sulfur atoms from cysteine and inorganic sulfide, and that are commonly arranged as Fe2S2 or Fe4S4 clusters.


A cofactor that is composed of an Fe(II) ion coordinated by a porphyrin ring.


Regulatory regions in mRNA, often in the 5′ untranslated region, that function to modulate gene expression in response to the binding of a small molecule.


The binding of a non-cognate metal to a protein, which often leads to inactivation or dysfunction.

P-type ATPases

Members of a family of membrane-associated ion pumps in which ion transport is coupled to the hydrolysis of ATP.

Nutritional immunity

A component of the host immune response in which metal availability is restricted to starve pathogens and inhibit their growth.


The ligand-bound state of a transcriptional repressor protein.


A phenomenon found in proteins that have multiple ligand-binding sites, in which ligand binding at one site positively or negatively affects ligand binding at the remaining sites.


A protein or secondary RNA structure that enables readthrough of transcription termination signals.


Secreted, low-molecular-weight Fe(III)-chelating molecules that are produced in response to conditions of low iron.


A post-translational modification found in members of the phylum Actinobacteria that targets proteins for degradation.

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Chandrangsu, P., Rensing, C. & Helmann, J. Metal homeostasis and resistance in bacteria. Nat Rev Microbiol 15, 338–350 (2017).

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