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  • Review Article
  • Published:

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.

Abstract

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.

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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.

References

  1. Merchant, S. S. & Helmann, J. D. Elemental economy: microbial strategies for optimizing growth in the face of nutrient limitation. Adv. Microb. Physiol. 60, 91–210 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Hood, M. I. & Skaar, E. P. Nutritional immunity: transition metals at the pathogen–host interface. Nat. Rev. Microbiol. 10, 525–537 (2012).

    CAS  PubMed  Google Scholar 

  3. Djoko, K. Y., Ong, C. L., Walker, M. J. & McEwan, A. G. The role of copper and zinc toxicity in innate immune defense against bacterial pathogens. J. Biol. Chem. 290, 18954–18961 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Ma, Z., Jacobsen, F. E. & Giedroc, D. P. Coordination chemistry of bacterial metal transport and sensing. Chem. Rev. 109, 4644–4681 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Waldron, K. J., Rutherford, J. C., Ford, D. & Robinson, N. J. Metalloproteins and metal sensing. Nature 460, 823–830 (2009).

    CAS  PubMed  Google Scholar 

  6. Mettert, E. L. & Kiley, P. J. Fe–S proteins that regulate gene expression. Biochim. Biophys. Acta 1853, 1284–1293 (2015).

    CAS  PubMed  Google Scholar 

  7. O'Brian, M. R. Perception and homeostatic control of iron in the rhizobia and related bacteria. Annu. Rev. Microbiol. 69, 229–245 (2015).

    CAS  PubMed  Google Scholar 

  8. Cromie, M. J., Shi, Y., Latifi, T. & Groisman, E. A. An RNA sensor for intracellular Mg2+. Cell 125, 71–84 (2006).

    CAS  PubMed  Google Scholar 

  9. Price, I. R., Gaballa, A., Ding, F., Helmann, J. D. & Ke, A. Mn2+-sensing mechanisms of yybP-ykoY orphan riboswitches. Mol. Cell 57, 1110–1123 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Dambach, M. et al. The ubiquitous yybP-ykoY riboswitch is a manganese-responsive regulatory element. Mol. Cell 57, 1099–1109 (2015). Together with reference 9, this study provides evidence for the ability of riboswitches to specifically sense Mn( II ) to regulate genes that are involved in metal homeostasis.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Nies, D. H. Efflux-mediated heavy metal resistance in prokaryotes. FEMS Microbiol. Rev. 27, 313–339 (2003).

    CAS  PubMed  Google Scholar 

  12. Colvin, R. A., Holmes, W. R., Fontaine, C. P. & Maret, W. Cytosolic zinc buffering and muffling: their role in intracellular zinc homeostasis. Metallomics 2, 306–317 (2010).

    CAS  PubMed  Google Scholar 

  13. Capdevila, D. A., Wang, J. & Giedroc, D. P. Bacterial strategies to maintain zinc metallostasis at the host–pathogen interface. J. Biol. Chem. 291, 20858–20868 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Sankaran, B. et al. Zinc-independent folate biosynthesis: genetic, biochemical, and structural investigations reveal new metal dependence for GTP cyclohydrolase IB. J. Bacteriol. 191, 6936–6949 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Natori, Y. et al. A fail-safe system for the ribosome under zinc-limiting conditions in Bacillus subtilis. Mol. Microbiol. 63, 294–307 (2007).

    CAS  PubMed  Google Scholar 

  16. Martin, J. E. & Imlay, J. A. The alternative aerobic ribonucleotide reductase of Escherichia coli, NrdEF, is a manganese-dependent enzyme that enables cell replication during periods of iron starvation. Mol. Microbiol. 80, 319–334 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Imlay, J. A. The mismetallation of enzymes during oxidative stress. J. Biol. Chem. 289, 28121–28128 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Huang, X., Shin, J. H., Pinochet-Barros, A., Su, T. T. & Helmann, J. D. Bacillus subtilis MntR coordinates the transcriptional regulation of manganese uptake and efflux systems. Mol. Microbiol. 103, 253–268 (2016). This study documents the ability of the Mn( II ) sensor MntR to function as both a repressor (of uptake functions) and a direct transcriptional activator of efflux.

    PubMed Central  PubMed  Google Scholar 

  19. Waters, L. S., Sandoval, M. & Storz, G. The Escherichia coli MntR miniregulon includes genes encoding a small protein and an efflux pump required for manganese homeostasis. J. Bacteriol. 193, 5887–5897 (2011).

    PubMed Central  PubMed  Google Scholar 

  20. Rosch, J. W., Gao, G., Ridout, G., Wang, Y. D. & Tuomanen, E. I. Role of the manganese efflux system mntE for signalling and pathogenesis in Streptococcus pneumoniae. Mol. Microbiol. 72, 12–25 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Hantke, K. Bacterial zinc transporters and regulators. Biometals 14, 239–249 (2001).

    CAS  PubMed  Google Scholar 

  22. Rensing, C. & Grass, G. Escherichia coli mechanisms of copper homeostasis in a changing environment. FEMS Microbiol. Rev. 27, 197–213 (2003).

    CAS  PubMed  Google Scholar 

  23. Guan, G. et al. PfeT, a P1B4-type ATPase, effluxes ferrous iron and protects Bacillus subtilis against iron intoxication. Mol. Microbiol. 98, 787–803 (2015). This study presents evidence for a role of P-type ATPases in the efflux of Fe( II ) from the cytosol as a mechanism to protect cells against both reactive oxygen species and iron intoxication.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Pi, H., Patel, S. J., Arguello, J. M. & Helmann, J. D. The Listeria monocytogenes Fur-regulated virulence protein FrvA is an Fe(II) efflux P1B4-type ATPase. Mol. Microbiol. 100, 1066–1079 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Botella, H. et al. Mycobacterial P1-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe 10, 248–259 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Patel, S. J. et al. Fine-tuning of substrate affinity leads to alternative roles of Mycobacterium tuberculosis Fe2+-ATPases. J. Biol. Chem. 291, 11529–11539 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Weinberg, E. D. Nutritional immunity. Host's attempt to withold iron from microbial invaders. JAMA 231, 39–41 (1975).

    CAS  PubMed  Google Scholar 

  28. Skaar, E. P. & Raffatellu, M. Metals in infectious diseases and nutritional immunity. Metallomics 7, 926–928 (2015).

    PubMed  Google Scholar 

  29. Sabine, D. B. & Vaselekos, J. Trace element requirements of Lactobacillus acidophilus. Nature 214, 520 (1967).

    CAS  PubMed  Google Scholar 

  30. Posey, J. E. & Gherardini, F. C. Lack of a role for iron in the Lyme disease pathogen. Science 288, 1651–1653 (2000).

    CAS  PubMed  Google Scholar 

  31. Anjem, A., Varghese, S. & Imlay, J. A. Manganese import is a key element of the OxyR response to hydrogen peroxide in Escherichia coli. Mol. Microbiol. 72, 844–858 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Vasantha, N. & Freese, E. The role of manganese in growth and sporulation of Bacillus subtilis. J. Gen. Microbiol. 112, 329–336 (1979).

    CAS  PubMed  Google Scholar 

  33. Waldron, K. J. & Robinson, N. J. How do bacterial cells ensure that metalloproteins get the correct metal? Nat. Rev. Microbiol. 7, 25–35 (2009).

    CAS  PubMed  Google Scholar 

  34. Gaballa, A. & Helmann, J. D. Identification of a zinc-specific metalloregulatory protein, Zur, controlling zinc transport operons in Bacillus subtilis. J. Bacteriol. 180, 5815–5821 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Moore, C. M. & Helmann, J. D. Metal ion homeostasis in Bacillus subtilis. Curr. Opin. Microbiol. 8, 188–195 (2005).

    CAS  PubMed  Google Scholar 

  36. Bsat, N., Herbig, A., Casillas-Martinez, L., Setlow, P. & Helmann, J. D. Bacillus subtilis contains multiple Fur homologues: identification of the iron uptake (Fur) and peroxide regulon (PerR) repressors. Mol. Microbiol. 29, 189–198 (1998).

    CAS  PubMed  Google Scholar 

  37. Que, Q. & Helmann, J. D. Manganese homeostasis in Bacillus subtilis is regulated by MntR, a bifunctional regulator related to the diphtheria toxin repressor family of proteins. Mol. Microbiol. 35, 1454–1468 (2000).

    CAS  PubMed  Google Scholar 

  38. Hantke, K. Cloning of the repressor protein gene of iron-regulated systems in Escherichia coli K12. Mol. Gen. Genet. 197, 337–341 (1984).

    CAS  PubMed  Google Scholar 

  39. Deng, Z. et al. Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator. Nat. Commun. 6, 7642 (2015).

    PubMed  Google Scholar 

  40. Dian, C. et al. The structure of the Helicobacter pylori ferric uptake regulator Fur reveals three functional metal binding sites. Mol. Microbiol. 79, 1260–1275 (2011).

    CAS  PubMed  Google Scholar 

  41. Butcher, J., Sarvan, S., Brunzelle, J. S., Couture, J. F. & Stintzi, A. Structure and regulon of Campylobacter jejuni ferric uptake regulator Fur define apo-Fur regulation. Proc. Natl Acad. Sci. USA 109, 10047–10052 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sheikh, M. A. & Taylor, G. L. Crystal structure of the Vibrio cholerae ferric uptake regulator (Fur) reveals insights into metal co-ordination. Mol. Microbiol. 72, 1208–1220 (2009).

    CAS  PubMed  Google Scholar 

  43. Pohl, E. et al. Architecture of a protein central to iron homeostasis: crystal structure and spectroscopic analysis of the ferric uptake regulator. Mol. Microbiol. 47, 903–915 (2003).

    CAS  PubMed  Google Scholar 

  44. Gaballa, A., MacLellan, S. & Helmann, J. D. Transcription activation by the siderophore sensor Btr is mediated by ligand-dependent stimulation of promoter clearance. Nucleic Acids Res. 40, 3585–3595 (2012).

    CAS  PubMed  Google Scholar 

  45. Lee, J. W. & Helmann, J. D. Functional specialization within the Fur family of metalloregulators. Biometals 20, 485–499 (2007).

    CAS  PubMed  Google Scholar 

  46. Funahashi, T. et al. Characterization of Vibrio parahaemolyticus manganese-resistant mutants in reference to the function of the ferric uptake regulatory protein. Microbiol. Immunol. 44, 963–970 (2000).

    CAS  PubMed  Google Scholar 

  47. Benson, H. P., LeVier, K. & Guerinot, M. L. A dominant-negative fur mutation in Bradyrhizobium japonicum. J. Bacteriol. 186, 1409–1414 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Hantke, K. Selection procedure for deregulated iron transport mutants (fur) in Escherichia coli K 12: fur not only affects iron metabolism. Mol. Gen. Genet. 210, 135–139 (1987).

    CAS  PubMed  Google Scholar 

  49. Merchant, A. T. & Spatafora, G. A. A role for the DtxR family of metalloregulators in Gram-positive pathogenesis. Mol. Oral Microbiol. 29, 1–10 (2014).

    CAS  PubMed  Google Scholar 

  50. Kliegman, J. I., Griner, S. L., Helmann, J. D., Brennan, R. G. & Glasfeld, A. Structural basis for the metal-selective activation of the manganese transport regulator of Bacillus subtilis. Biochemistry 45, 3493–3505 (2006).

    CAS  PubMed  Google Scholar 

  51. McGuire, A. M. et al. Roles of the A and C sites in the manganese-specific activation of MntR. Biochemistry 52, 701–713 (2013).

    CAS  PubMed  Google Scholar 

  52. Patzer, S. I. & Hantke, K. Dual repression by Fe2+–Fur and Mn2+–MntR of the mntH gene, encoding an NRAMP-like Mn2+ transporter in Escherichia coli. J. Bacteriol. 183, 4806–4813 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Ikeda, J. S., Janakiraman, A., Kehres, D. G., Maguire, M. E. & Slauch, J. M. Transcriptional regulation of sitABCD of Salmonella enterica serovar Typhimurium by MntR and Fur. J. Bacteriol. 187, 912–922 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Patzer, S. I. & Hantke, K. The ZnuABC high-affinity zinc uptake system and its regulator Zur in Escherichia coli. Mol. Microbiol. 28, 1199–1210 (1998).

    CAS  PubMed  Google Scholar 

  55. Ma, Z., Lee, J. W. & Helmann, J. D. Identification of altered function alleles that affect Bacillus subtilis PerR metal ion selectivity. Nucleic Acids Res. 39, 5036–5044 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Moore, C. M., Gaballa, A., Hui, M., Ye, R. W. & Helmann, J. D. Genetic and physiological responses of Bacillus subtilis to metal ion stress. Mol. Microbiol. 57, 27–40 (2005).

    CAS  PubMed  Google Scholar 

  57. Pennella, M. A., Arunkumar, A. I. & Giedroc, D. P. Individual metal ligands play distinct functional roles in the zinc sensor Staphylococcus aureus CzrA. J. Mol. Biol. 356, 1124–1136 (2006).

    CAS  PubMed  Google Scholar 

  58. Andrews, S. C., Robinson, A. K. & Rodriguez-Quinones, F. Bacterial iron homeostasis. FEMS Microbiol. Rev. 27, 215–237 (2003).

    CAS  PubMed  Google Scholar 

  59. Hamza, I., Qi, Z., King, N. D. & O'Brian, M. R. Fur-independent regulation of iron metabolism by Irr in Bradyrhizobium japonicum. Microbiology 146, 669–676 (2000).

    CAS  PubMed  Google Scholar 

  60. Qi, Z. & O'Brian, M. R. Interaction between the bacterial iron response regulator and ferrochelatase mediates genetic control of heme biosynthesis. Mol. Cell 9, 155–162 (2002).

    CAS  PubMed  Google Scholar 

  61. Rudolph, G. et al. The iron control element, acting in positive and negative control of iron-regulated Bradyrhizobium japonicum genes, is a target for the Irr protein. J. Bacteriol. 188, 733–744 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Ferreira, G. C. Heme biosynthesis: biochemistry, molecular biology, and relationship to disease. J. Bioenerg. Biomembr. 27, 147–150 (1995).

    CAS  PubMed  Google Scholar 

  63. Schwartz, C. J. et al. IscR, an Fe–S cluster-containing transcription factor, represses expression of Escherichia coli genes encoding Fe–S cluster assembly proteins. Proc. Natl Acad. Sci. USA 98, 14895–14900 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Giel, J. L., Rodionov, D., Liu, M., Blattner, F. R. & Kiley, P. J. IscR-dependent gene expression links iron–sulphur cluster assembly to the control of O2-regulated genes in Escherichia coli. Mol. Microbiol. 60, 1058–1075 (2006).

    CAS  PubMed  Google Scholar 

  65. Rajagopalan, S. et al. Studies of IscR reveal a unique mechanism for metal-dependent regulation of DNA binding specificity. Nat. Struct. Mol. Biol. 20, 740–747 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Dann, C. E. et al. Structure and mechanism of a metal-sensing regulatory RNA. Cell 130, 878–892 (2007).

    CAS  PubMed  Google Scholar 

  67. Hattori, M. et al. Mg2+-dependent gating of bacterial MgtE channel underlies Mg2+ homeostasis. EMBO J. 28, 3602–3612 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Ma, Z., Faulkner, M. J. & Helmann, J. D. Origins of specificity and cross-talk in metal ion sensing by Bacillus subtilis Fur. Mol. Microbiol. 86, 1144–1155 (2012). This study demonstrates that altering the level of a metalloregulatory protein can trigger crosstalk, in which inappropriate repression of iron uptake (through the sensing of Mn( II ) by Fur) can trigger iron starvation.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Furukawa, K. et al. Bacterial riboswitches cooperatively bind Ni2+ or Co2+ ions and control expression of heavy metal transporters. Mol. Cell 57, 1088–1098 (2015). This study defines an additional class of riboswitches that respond to metal ions, including Ni( II ), Co( II ) and perhaps other metals.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Banerjee, R. V., Johnston, N. L., Sobeski, J. K., Datta, P. & Matthews, R. G. Cloning and sequence analysis of the Escherichia coli metH gene encoding cobalamin-dependent methionine synthase and isolation of a tryptic fragment containing the cobalamin-binding domain. J. Biol. Chem. 264, 13888–13895 (1989).

    CAS  PubMed  Google Scholar 

  71. Nahvi, A. et al. Genetic control by a metabolite binding mRNA. Chem. Biol. 9, 1043 (2002).

    CAS  PubMed  Google Scholar 

  72. Rodionov, D. A., Hebbeln, P., Gelfand, M. S. & Eitinger, T. Comparative and functional genomic analysis of prokaryotic nickel and cobalt uptake transporters: evidence for a novel group of ATP-binding cassette transporters. J. Bacteriol. 188, 317–327 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Gaballa, A. et al. The Bacillus subtilis iron-sparing response is mediated by a Fur-regulated small RNA and three small, basic proteins. Proc. Natl Acad. Sci. USA 105, 11927–11932 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Masse, E. & Gottesman, S. A small RNA regulates the expression of genes involved in iron metabolism in Escherichia coli. Proc. Natl Acad. Sci. USA 99, 4620–4625 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Baichoo, N., Wang, T., Ye, R. & Helmann, J. D. Global analysis of the Bacillus subtilis Fur regulon and the iron starvation stimulon. Mol. Microbiol. 45, 1613–1629 (2002).

    CAS  PubMed  Google Scholar 

  76. Yoch, D. C. & Valentine, R. C. Ferredoxins and flavodoxins of bacteria. Annu. Rev. Microbiol. 26, 139–162 (1972).

    CAS  PubMed  Google Scholar 

  77. Erdner, D. L. & Anderson, D. M. Ferredoxin and flavodoxin as biochemical indicators of iron limitation during open-ocean iron enrichment. Limnol. Oceanogr. 44, 1609–1615 (1999).

    CAS  Google Scholar 

  78. Smaldone, G. T. et al. A global investigation of the Bacillus subtilis iron-sparing response identifies major changes in metabolism. J. Bacteriol. 194, 2594–2605 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Masse, E. & Arguin, M. Ironing out the problem: new mechanisms of iron homeostasis. Trends Biochem. Sci. 30, 462–468 (2005).

    CAS  PubMed  Google Scholar 

  80. Yost, F. J. & Fridovich, I. An iron-containing superoxide dismutase from Escherichia coli. J. Biol. Chem. 248, 4905–4908 (1973).

    CAS  PubMed  Google Scholar 

  81. Keele, B. B., McCord, J. M. & Fridovich, I. Superoxide dismutase from Escherichia coli B. A new manganese-containing enzyme. J. Biol. Chem. 245, 6176–6181 (1970).

    CAS  PubMed  Google Scholar 

  82. Fee, J. A. Regulation of sod genes in Escherichia coli: relevance to superoxide dismutase function. Mol. Microbiol. 5, 2599–2610 (1991).

    CAS  PubMed  Google Scholar 

  83. Andrews, S. C. Making DNA without iron — induction of a manganese-dependent ribonucleotide reductase in response to iron starvation. Mol. Microbiol. 80, 286–289 (2011).

    CAS  PubMed  Google Scholar 

  84. Masse, E., Vanderpool, C. K. & Gottesman, S. Effect of RyhB small RNA on global iron use in Escherichia coli. J. Bacteriol. 187, 6962–6971 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Mielcarek, A., Blauenburg, B., Miethke, M. & Marahiel, M. A. Molecular insights into frataxin-mediated iron supply for heme biosynthesis in Bacillus subtilis. PLoS ONE 10, e0122538 (2015).

    PubMed Central  PubMed  Google Scholar 

  86. Gaballa, A., Wang, T., Ye, R. W. & Helmann, J. D. Functional analysis of the Bacillus subtilis Zur regulon. J. Bacteriol. 184, 6508–6514 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Akanuma, G., Nanamiya, H., Natori, Y., Nomura, N. & Kawamura, F. Liberation of zinc-containing L31 (RpmE) from ribosomes by its paralogous gene product, YtiA, in Bacillus subtilis. J. Bacteriol. 188, 2715–2720 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Nanamiya, H. et al. Zinc is a key factor in controlling alternation of two types of L31 protein in the Bacillus subtilis ribosome. Mol. Microbiol. 52, 273–283 (2004).

    CAS  PubMed  Google Scholar 

  89. Gabriel, S. E. & Helmann, J. D. Contributions of Zur-controlled ribosomal proteins to growth under zinc starvation conditions. J. Bacteriol. 191, 6116–6122 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Shin, J. H. & Helmann, J. D. Molecular logic of the Zur-regulated zinc deprivation response in Bacillus subtilis. Nat. Commun. 7, 12612 (2016). This study demonstrates that the imposition of Zn( II ) deficiency leads first to the mobilization of Zn( II ) ions from internal stores (associated with ribosomal proteins); second, to the activation of high-affinity import; and, third, to the replacement of proteins that have Zn( II )-dependent functions with proteins that lack a requirement for Zn( II).

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Shin, J. H. et al. Graded expression of zinc-responsive genes through two regulatory zinc-binding sites in Zur. Proc. Natl Acad. Sci. USA 108, 5045–5050 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Gilston, B. A. et al. Structural and mechanistic basis of zinc regulation across the E. coli Zur regulon. PLoS Biol. 12, e1001987 (2014). This study provides structural insights into the nature of protein–protein interactions that contribute to the cooperative activity of Fur family proteins (in this case, Zur) when binding to DNA.

    PubMed Central  PubMed  Google Scholar 

  93. Beauchene, N. A. et al. Impact of anaerobiosis on expression of the iron-responsive Fur and RyhB regulons. mBio 6, e01947-15 (2015).

    PubMed Central  PubMed  Google Scholar 

  94. German, N., Doyscher, D. & Rensing, C. Bacterial killing in macrophages and amoeba: do they all use a brass dagger? Future Microbiol. 8, 1257–1264 (2013).

    CAS  PubMed  Google Scholar 

  95. Outten, C. E. & O'Halloran, T. V. Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 292, 2488–2492 (2001).

    CAS  PubMed  Google Scholar 

  96. Ma, Z. et al. Bacillithiol is a major buffer of the labile zinc pool in Bacillus subtilis. Mol. Microbiol. 94, 756–770 (2014). This study identifies bacillithiol, which is a major low-molecular-weight thiol, as an intracellular buffer for Zn( II ) and possibly other metal ions, thereby highlighting the role of cytosolic ligands in the maintenance of the labile metal pool.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Newton, G. L. et al. Bacillithiol is an antioxidant thiol produced in Bacilli. Nat. Chem. Biol. 5, 625–627 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Sharma, S. V. et al. Chemical and chemoenzymatic syntheses of bacillithiol: a unique low-molecular-weight thiol amongst low G+C Gram-positive bacteria. Angew. Chem. Int. Ed. 50, 7101–7104 (2011).

    CAS  Google Scholar 

  99. Helbig, K., Bleuel, C., Krauss, G. J. & Nies, D. H. Glutathione and transition-metal homeostasis in Escherichia coli. J. Bacteriol. 190, 5431–5438 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Maret, W. Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc. Natl Acad. Sci. USA 91, 237–241 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nairn, B. L. et al. The response of Acinetobacter baumannii to zinc starvation. Cell Host Microbe 19, 826–836 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Fung, D. K., Lau, W. Y., Chan, W. T. & Yan, A. Copper efflux is induced during anaerobic amino acid limitation in Escherichia coli to protect iron–sulfur cluster enzymes and biogenesis. J. Bacteriol. 195, 4556–4568 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Kay, K. L., Hamilton, C. J. & Le Brun, N. E. Mass spectrometry of B. subtilis CopZ: Cu(I)-binding and interactions with bacillithiol. Metallomics 8, 709–719 (2016).

    CAS  PubMed  Google Scholar 

  104. Potter, A. J., Trappetti, C. & Paton, J. C. Streptococcus pneumoniae uses glutathione to defend against oxidative stress and metal ion toxicity. J. Bacteriol. 194, 6248–6254 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Culotta, V. C. & Daly, M. J. Manganese complexes: diverse metabolic routes to oxidative stress resistance in prokaryotes and yeast. Antioxid. Redox Signal. 19, 933–944 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Bruch, E. M., Thomine, S., Tabares, L. C. & Un, S. Variations in Mn(II) speciation among organisms: what makes D. radiodurans different. Metallomics 7, 136–144 (2015).

    CAS  PubMed  Google Scholar 

  107. Sharma, A. et al. Responses of Mn2+ speciation in Deinococcus radiodurans and Escherichia coli to gamma-radiation by advanced paramagnetic resonance methods. Proc. Natl Acad. Sci. USA 110, 5945–5950 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Tabares, L. C. & Un, S. In situ determination of manganese(II) speciation in Deinococcus radiodurans by high magnetic field EPR: detection of high levels of Mn(II) bound to proteins. J. Biol. Chem. 288, 5050–5055 (2013). Together with references 105–107, this study highlights the role of low-molecular-weight complexes in buffering Mn( II ) in the bacterial cytosol in the form of complexes that may also have a protective role under oxidative stress conditions.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Tu, W. Y. et al. Cellular iron distribution in Bacillus anthracis. J. Bacteriol. 194, 932–940 (2012). This study provides a proteomic perspective on the identity and dynamics of the major iron pools in the cytosol, including the dominant roles of miniferritins and superoxide dismutases.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Andrews, S. C. Iron storage in bacteria. Adv. Microb. Physiol. 40, 281–351 (1998).

    CAS  PubMed  Google Scholar 

  111. Waidner, B. et al. Essential role of ferritin Pfr in Helicobacter pylori iron metabolism and gastric colonization. Infect. Immun. 70, 3923–3929 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Macedo, S. et al. The nature of the di-iron site in the bacterioferritin from Desulfovibrio desulfuricans. Nat. Struct. Biol. 10, 285–290 (2003).

    CAS  PubMed  Google Scholar 

  113. Carrondo, M. A. Ferritins, iron uptake and storage from the bacterioferritin viewpoint. EMBO J. 22, 1959–1968 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Yang, X., Le Brun, N. E., Thomson, A. J., Moore, G. R. & Chasteen, N. D. The iron oxidation and hydrolysis chemistry of Escherichia coli bacterioferritin. Biochemistry 39, 4915–4923 (2000).

    CAS  PubMed  Google Scholar 

  115. Kuberl, A., Polen, T. & Bott, M. The pupylation machinery is involved in iron homeostasis by targeting the iron storage protein ferritin. Proc. Natl Acad. Sci. USA 113, 4806–4811 (2016). This study shows that the molecular mechanisms that enable stored iron pools to be accessed in times of need involve the regulated degradation of ferritin proteins in C. glutamicum.

    PubMed  PubMed Central  Google Scholar 

  116. Beard, S. J., Hughes, M. N. & Poole, R. K. Inhibition of the cytochrome bd-terminated NADH oxidase system in Escherichia coli K-12 by divalent metal cations. FEMS Microbiol. Lett. 131, 205–210 (1995).

    CAS  PubMed  Google Scholar 

  117. Brekasis, D. & Paget, M. S. A novel sensor of NADH/NAD+ redox poise in Streptomyces coelicolor A3(2). EMBO J. 22, 4856–4865 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Alhasawi, A., Auger, C., Appanna, V. P., Chahma, M. & Appanna, V. D. Zinc toxicity and ATP production in Pseudomonas fluorescens. J. Appl. Microbiol. 117, 65–73 (2014).

    CAS  PubMed  Google Scholar 

  119. Chandrangsu, P. & Helmann, J. D. Intracellular Zn(II) intoxication leads to dysregulation of the PerR regulon resulting in heme toxicity in Bacillus subtilis. PLoS Genet. 12, e1006515 (2016).

    PubMed Central  PubMed  Google Scholar 

  120. Shepherd, M. et al. The cytochrome bd-I respiratory oxidase augments survival of multidrug-resistant Escherichia coli during infection. Sci. Rep. 6, 35285 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Mason, M. G. et al. Cytochrome bd confers nitric oxide resistance to Escherichia coli. Nat. Chem. Biol. 5, 94–96 (2009).

    CAS  PubMed  Google Scholar 

  122. Korshunov, S., Imlay, K. R. & Imlay, J. A. The cytochrome bd oxidase of Escherichia coli prevents respiratory inhibition by endogenous and exogenous hydrogen sulfide. Mol. Microbiol. 101, 62–77 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  123. McDevitt, C. A. et al. A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog. 7, e1002357 (2011). This study presents a mechanism for Zn( II ) toxicity that is based on the inhibition of Mn( II ) import as a consequence of mismetallation of a central protein that is involved in Mn( II ) uptake.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Takeda, H. et al. Structural basis for ion selectivity revealed by high-resolution crystal structure of Mg2+ channel MgtE. Nat. Commun. 5, 5374 (2014).

    CAS  PubMed  Google Scholar 

  125. Anjem, A. & Imlay, J. A. Mononuclear iron enzymes are primary targets of hydrogen peroxide stress. J. Biol. Chem. 287, 15544–15556 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Macomber, L. & Imlay, J. A. The iron–sulfur clusters of dehydratases are primary intracellular targets of copper toxicity. Proc. Natl Acad. Sci. USA 106, 8344–8349 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Xu, F. F. & Imlay, J. A. Silver(I), mercury(II), cadmium(II), and zinc(II) target exposed enzymic iron–sulfur clusters when they toxify Escherichia coli. Appl. Environ. Microbiol. 78, 3614–3621 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Chillappagari, S. et al. Copper stress affects iron homeostasis by destabilizing iron–sulfur cluster formation in Bacillus subtilis. J. Bacteriol. 192, 2512–2524 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Martin, J. E., Waters, L. S., Storz, G. & Imlay, J. A. The Escherichia coli small protein MntS and exporter MntP optimize the intracellular concentration of manganese. PLoS Genet. 11, e1004977 (2015). This study presents evidence that supports a mechanism of post-translational allosteric regulation of metal efflux activity to prevent metal depletion in the cytoplasm.

    PubMed Central  PubMed  Google Scholar 

  130. Begg, S. L. et al. Dysregulation of transition metal ion homeostasis is the molecular basis for cadmium toxicity in Streptococcus pneumoniae. Nat. Commun. 6, 6418 (2015). This study provides examples of the complex effects that toxic heavy metals can have on cytosolic metal pools and cell physiology.

    CAS  PubMed  Google Scholar 

  131. Lee, J. W. & Helmann, J. D. The PerR transcription factor senses H2O2 by metal-catalysed histidine oxidation. Nature 440, 363–367 (2006).

    CAS  PubMed  Google Scholar 

  132. Faulkner, M. J., Ma, Z., Fuangthong, M. & Helmann, J. D. Derepression of the Bacillus subtilis PerR peroxide stress response leads to iron deficiency. J. Bacteriol. 194, 1226–1235 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Wakeman, C. A. et al. Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus. Mol. Microbiol. 86, 1376–1392 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Liu, J. Z. et al. Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. Cell Host Microbe 11, 227–239 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Damo, S. M. et al. Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens. Proc. Natl Acad. Sci. USA 110, 3841–3846 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Gunshin, H. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482–488 (1997).

    CAS  PubMed  Google Scholar 

  137. White, C., Lee, J., Kambe, T., Fritsche, K. & Petris, M. J. A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J. Biol. Chem. 284, 33949–33956 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Kapetanovic, R. et al. Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages. FASEB J. 30, 1901–1912 (2016).

    CAS  PubMed  Google Scholar 

  139. Ong, C. L., Walker, M. J. & McEwan, A. G. Zinc disrupts central carbon metabolism and capsule biosynthesis in Streptococcus pyogenes. Sci. Rep. 5, 10799 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Francis, M. S. & Thomas, C. J. Mutants in the CtpA copper transporting P-type ATPase reduce virulence of Listeria monocytogenes. Microb. Pathog. 22, 67–78 (1997).

    CAS  PubMed  Google Scholar 

  141. Achard, M. E. et al. The multi-copper-ion oxidase CueO of Salmonella enterica serovar Typhimurium is required for systemic virulence. Infect. Immun. 78, 2312–2319 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Turner, A. G. et al. Manganese homeostasis in group A Streptococcus is critical for resistance to oxidative stress and virulence. mBio 6, e00278-15 (2015).

    PubMed Central  PubMed  Google Scholar 

  143. McLaughlin, H. P. et al. A putative P-type ATPase required for virulence and resistance to haem toxicity in Listeria monocytogenes. PLoS ONE 7, e30928 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Hubert, K. et al. ZnuD, a potential candidate for a simple and universal Neisseria meningitidis vaccine. Infect. Immun. 81, 1915–1927 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Anderson, A. S. et al. Staphylococcus aureus manganese transport protein C is a highly conserved cell surface protein that elicits protective immunity against S. aureus and Staphylococcus epidermidis. J. Infect. Dis. 205, 1688–1696 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Miyaji, E. N. et al. PsaA (pneumococcal surface adhesin A) and PspA (pneumococcal surface protein A) DNA vaccines induce humoral and cellular immune responses against Streptococcus pneumoniae. Vaccine 20, 805–812 (2001).

    CAS  PubMed  Google Scholar 

  147. Keyer, K. & Imlay, J. A. Superoxide accelerates DNA damage by elevating free-iron levels. Proc. Natl Acad. Sci. USA 93, 13635–13640 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Irving, H. & Williams, R. J. P. 637. The stability of transition-metal complexes. J. Chem. Soc. 1953, 3192–3210 (1953).

    Google Scholar 

  149. Foster, A. W., Osman, D. & Robinson, N. J. Metal preferences and metallation. J. Biol. Chem. 289, 28095–28103 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Braymer, J. J. & Giedroc, D. P. Recent developments in copper and zinc homeostasis in bacterial pathogens. Curr. Opin. Chem. Biol. 19, 59–66 (2014).

    CAS  PubMed  Google Scholar 

  151. Outten, F. W., Huffman, D. L., Hale, J. A. & O'Halloran, T. V. The independent cue and cus systems confer copper tolerance during aerobic and anaerobic growth in Escherichia coli. J. Biol. Chem. 276, 30670–30677 (2001).

    CAS  PubMed  Google Scholar 

  152. Rensing, C. & McDevitt, S. F. The copper metallome in prokaryotic cells. Met. Ions Life Sci. 12, 417–450 (2013).

    PubMed  Google Scholar 

  153. Maguire, M. E. & Cowan, J. A. Magnesium chemistry and biochemistry. Biometals 15, 203–210 (2002).

    CAS  PubMed  Google Scholar 

  154. Helmann, J. D. Specificity of metal sensing: iron and manganese homeostasis in Bacillus subtilis. J. Biol. Chem. 289, 28112–28120 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Lemire, J. A., Harrison, J. J. & Turner, R. J. Antimicrobial activity of metals: mechanisms, molecular targets and applications. Nat. Rev. Microbiol. 11, 371–384 (2013).

    CAS  PubMed  Google Scholar 

  156. Tottey, S. et al. Cyanobacterial metallochaperone inhibits deleterious side reactions of copper. Proc. Natl Acad. Sci. USA 109, 95–100 (2012).

    CAS  PubMed  Google Scholar 

  157. Guedon, E. & Helmann, J. D. Origins of metal ion selectivity in the DtxR/MntR family of metalloregulators. Mol. Microbiol. 48, 495–506 (2003).

    CAS  PubMed  Google Scholar 

  158. Cavet, J. S. et al. A nickel–cobalt-sensing ArsR–SmtB family repressor. Contributions of cytosol and effector binding sites to metal selectivity. J. Biol. Chem. 277, 38441–38448 (2002).

    CAS  PubMed  Google Scholar 

  159. Harvie, D. R. et al. Predicting metals sensed by ArsR–SmtB repressors: allosteric interference by a non-effector metal. Mol. Microbiol. 59, 1341–1356 (2006).

    CAS  PubMed  Google Scholar 

  160. Ma, Z., Cowart, D. M., Scott, R. A. & Giedroc, D. P. Molecular insights into the metal selectivity of the copper(I)-sensing repressor CsoR from Bacillus subtilis. Biochemistry 48, 3325–3334 (2009).

    CAS  PubMed  Google Scholar 

  161. Dalmas, O., Sompornpisut, P., Bezanilla, F. & Perozo, E. Molecular mechanism of Mg2+-dependent gating in CorA. Nat. Commun. 5, 3590 (2014).

    PubMed  Google Scholar 

  162. Hattori, M., Tanaka, Y., Fukai, S., Ishitani, R. & Nureki, O. Crystal structure of the MgtE Mg2+ transporter. Nature 448, 1072–1075 (2007).

    CAS  PubMed  Google Scholar 

  163. Zhao, H. & Eide, D. The yeast ZRT1 gene encodes the zinc transporter protein of a high-affinity uptake system induced by zinc limitation. Proc. Natl Acad. Sci. USA 93, 2454–2458 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. MacDiarmid, C. W., Milanick, M. A. & Eide, D. J. Induction of the ZRC1 metal tolerance gene in zinc-limited yeast confers resistance to zinc shock. J. Biol. Chem. 278, 15065–15072 (2003).

    CAS  PubMed  Google Scholar 

  165. Knutson, M. D., Oukka, M., Koss, L. M., Aydemir, F. & Wessling-Resnick, M. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc. Natl Acad. Sci. USA 102, 1324–1328 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Stafford, S. L. et al. Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper. Biosci. Rep. 33, e00049 (2013).

    PubMed Central  PubMed  Google Scholar 

  167. Raimunda, D., Long, J. E., Sassetti, C. M. & Arguello, J. M. Role in metal homeostasis of CtpD, a Co2+ transporting P1B4-ATPase of Mycobacterium smegmatis. Mol. Microbiol. 84, 1139–1149 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Hao, X. et al. Survival in amoeba — a major selection pressure on the presence of bacterial copper and zinc resistance determinants? Identification of a “copper pathogenicity island”. Appl. Microbiol. Biotechnol. 99, 5817–5824 (2015).

    CAS  PubMed  Google Scholar 

  169. Buracco, S. et al. Dictyostelium Nramp1, which is structurally and functionally similar to mammalian DMT1 transporter, mediates phagosomal iron efflux. J. Cell Sci. 128, 3304–3316 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Peracino, B., Buracco, S. & Bozzaro, S. The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum. J. Cell Sci. 126, 301–311 (2013).

    CAS  PubMed  Google Scholar 

  171. Burlando, B. et al. Occurrence of Cu-ATPase in Dictyostelium: possible role in resistance to copper. Biochem. Biophys. Res. Commun. 291, 476–483 (2002).

    CAS  PubMed  Google Scholar 

  172. Hao, X. et al. A role for copper in protozoan grazing — two billion years selecting for bacterial copper resistance. Mol. Microbiol. 102, 628–641 (2016). This study provides evidence that amoebae use copper intoxication as a strategy for killing bacterial prey, thereby imposing selection for copper resistance determinants.

    CAS  PubMed  Google Scholar 

  173. Fields, B. S. The molecular ecology of legionellae. Trends Microbiol. 4, 286–290 (1996).

    CAS  PubMed  Google Scholar 

  174. Hilbi, H., Segal, G. & Shuman, H. A. Icm/dot-dependent upregulation of phagocytosis by Legionella pneumophila. Mol. Microbiol. 42, 603–617 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

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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Glossary

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.

Haem

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

Riboswitches

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.

Mismetallation

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.

Holorepressor

The ligand-bound state of a transcriptional repressor protein.

Cooperativity

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.

Antiterminator

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

Siderophores

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

Pupylation

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). https://doi.org/10.1038/nrmicro.2017.15

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