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Nutritional immunity: the battle for nutrient metals at the host–pathogen interface

Nature Reviews Microbiology volume 20, pages 657–670 (2022)Cite this article

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Abstract

Trace metals are essential micronutrients required for survival across all kingdoms of life. From bacteria to animals, metals have critical roles as both structural and catalytic cofactors for an estimated third of the proteome, representing a major contributor to the maintenance of cellular homeostasis. The reactivity of metal ions engenders them with the ability to promote enzyme catalysis and stabilize reaction intermediates. However, these properties render metals toxic at high concentrations and, therefore, metal levels must be tightly regulated. Having evolved in close association with bacteria, vertebrate hosts have developed numerous strategies of metal limitation and intoxication that prevent bacterial proliferation, a process termed nutritional immunity. In turn, bacterial pathogens have evolved adaptive mechanisms to survive in conditions of metal depletion or excess. In this Review, we discuss mechanisms by which nutrient metals shape the interactions between bacterial pathogens and animal hosts. We explore the cell-specific and tissue-specific roles of distinct trace metals in shaping bacterial infections, as well as implications for future research and new therapeutic development.

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Fig. 1: Host Fe-limitation strategies.
Fig. 2: Bacterial Fe homeostasis at the host–pathogen interface.
Fig. 3: Host sequestration of Zn and Mn.
Fig. 4: Bacterial acquisition of Zn and Mn.
Fig. 5: Metal intoxication.
Fig. 6: Therapeutic interventions harnessing nutritional immunity.

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References

  1. Van Gossum, A. & Neve, J. Trace element deficiency and toxicity. Curr. Opin. Clin. Nutr. Metab. Care 1, 499–507 (1998).

    Article  PubMed  Google Scholar 

  2. Andreini, C., Bertini, I., Cavallaro, G., Holliday, G. L. & Thornton, J. M. Metal ions in biological catalysis: from enzyme databases to general principles. J. Biol. Inorg. Chem. 13, 1205–1218 (2008).

    Article  PubMed  CAS  Google Scholar 

  3. Maret, W. Metalloproteomics, metalloproteomes, and the annotation of metalloproteins. Metallomics 2, 117–125 (2010).

    Article  PubMed  CAS  Google Scholar 

  4. Andreini, C., Banci, L., Bertini, I. & Rosato, A. Counting the zinc-proteins encoded in the human genome. J. Proteome Res. 5, 196–201 (2006).

    Article  PubMed  CAS  Google Scholar 

  5. Lopez, C. A. & Skaar, E. P. The impact of dietary transition metals on host–bacterial interactions. Cell Host Microbe 23, 737–748 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Antelo, G. T., Vila, A. J., Giedroc, D. P. & Capdevila, D. A. Molecular evolution of transition metal bioavailability at the host–pathogen interface. Trends Microbiol. 29, 441–457 (2021).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Cunrath, O., Geoffroy, V. A. & Schalk, I. J. Metallome of Pseudomonas aeruginosa: a role for siderophores. Env. Microbiol. 18, 3258–3267 (2016).

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Wardman, P. & Candeias, L. P. Fenton chemistry: an introduction. Radiat. Res. 145, 523–531 (1996).

    Article  PubMed  CAS  Google Scholar 

  12. Haschka, D., Hoffmann, A. & Weiss, G. Iron in immune cell function and host defense. Semin. Cell Dev. Biol. 115, 27–36 (2021).

    Article  PubMed  CAS  Google Scholar 

  13. Choby, J. E. & Skaar, E. P. Heme synthesis and acquisition in bacterial pathogens. J. Mol. Biol. 428, 3408–3428 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Iatsenko, I., Marra, A., Boquete, J. P., Pena, J. & Lemaitre, B. Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 117, 7317–7325 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Ganz, T. Iron and infection. Int. J. Hematol. 107, 7–15 (2018).

    Article  PubMed  CAS  Google Scholar 

  16. Cellier, M. F., Courville, P. & Campion, C. Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect. 9, 1662–1670 (2007).

    Article  PubMed  CAS  Google Scholar 

  17. Brenz, Y., Ohnezeit, D., Winther-Larsen, H. C. & Hagedorn, M. Nramp1 and NrampB contribute to resistance against Francisella in Dictyostelium. Front. Cell Infect. Microbiol. 7, 282 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Cunrath, O. & Bumann, D. Host resistance factor SLC11A1 restricts Salmonella growth through magnesium deprivation. Science 366, 995–999 (2019).

    Article  PubMed  CAS  Google Scholar 

  19. Wessling-Resnick, M. Nramp1 and other transporters involved in metal withholding during infection. J. Biol. Chem. 290, 18984–18990 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Monteith, A. J. & Skaar, E. P. The impact of metal availability on immune function during infection. Trends Endocrinol. Metab. 32, 916–928 (2021).

    Article  PubMed  CAS  Google Scholar 

  21. Singh, V. et al. Microbiota-inducible innate immune, siderophore binding protein lipocalin 2 is critical for intestinal homeostasis. Cell Mol. Gastroenterol. Hepatol. 2, 482–498.e6 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hantke, K. Iron and metal regulation in bacteria. Curr. Opin. Microbiol. 4, 172–177 (2001).

    Article  PubMed  CAS  Google Scholar 

  23. Wakeman, C. A. & Skaar, E. P. Metalloregulation of Gram-positive pathogen physiology. Curr. Opin. Microbiol. 15, 169–174 (2012).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Gray-Owen, S. D. & Schryvers, A. B. Bacterial transferrin and lactoferrin receptors. Trends Microbiol. 4, 185–191 (1996).

    Article  PubMed  CAS  Google Scholar 

  27. Ostan, N. K. et al. Lactoferrin binding protein B — a bi-functional bacterial receptor protein. PLoS Pathog. 13, e1006244 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Linhartova, I. et al. RTX proteins: a highly diverse family secreted by a common mechanism. FEMS Microbiol. Rev. 34, 1076–1112 (2010).

    Article  PubMed  CAS  Google Scholar 

  29. Martins, R. et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat. Immunol. 17, 1361–1372 (2016).

    Article  PubMed  CAS  Google Scholar 

  30. Anzaldi, L. L. & Skaar, E. P. Overcoming the heme paradox: heme toxicity and tolerance in bacterial pathogens. Infect. Immun. 78, 4977–4989 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Richard, K. L., Kelley, B. R. & Johnson, J. G. Heme uptake and utilization by Gram-negative bacterial pathogens. Front. Cell Infect. Microbiol. 9, 81 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Brimberry, M., Toma, M. A., Hines, K. M. & Lanzilotta, W. N. HutW from Vibrio cholerae is an anaerobic heme-degrading enzyme with unique functional properties. Biochemistry 60, 699–710 (2021).

    Article  PubMed  CAS  Google Scholar 

  33. Maresso, A. W., Chapa, T. J. & Schneewind, O. Surface protein IsdC and Sortase B are required for heme-iron scavenging of Bacillus anthracis. J. Bacteriol. 188, 8145–8152 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Maresso, A. W., Garufi, G. & Schneewind, O. Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin. PLoS Pathog. 4, e1000132 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Skaar, E. P., Gaspar, A. H. & Schneewind, O. Bacillus anthracis IsdG, a heme-degrading monooxygenase. J. Bacteriol. 188, 1071–1080 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Farrand, A. J. et al. An iron-regulated autolysin remodels the cell wall to facilitate heme acquisition in Staphylococcus lugdunensis. Infect. Immun. 83, 3578–3589 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Pishchany, G. et al. IsdB-dependent hemoglobin binding is required for acquisition of heme by Staphylococcus aureus. J. Infect. Dis. 209, 1764–1772 (2014).

    Article  PubMed  CAS  Google Scholar 

  38. Jochim, A. et al. An ECF-type transporter scavenges heme to overcome iron-limitation in Staphylococcus lugdunensis. eLife https://doi.org/10.7554/eLife.57322 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Allen, C. E. & Schmitt, M. P. HtaA is an iron-regulated hemin binding protein involved in the utilization of heme iron in Corynebacterium diphtheriae. J. Bacteriol. 191, 2638–2648 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Zhu, H., Liu, M. & Lei, B. The surface protein Shr of Streptococcus pyogenes binds heme and transfers it to the streptococcal heme-binding protein Shp. BMC Microbiol. 8, 15 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Zygiel, E. M., Obisesan, A. O., Nelson, C. E., Oglesby, A. G. & Nolan, E. M. Heme protects Pseudomonas aeruginosa and Staphylococcus aureus from calprotectin-induced iron starvation. J. Biol. Chem. 296, 100160 (2021).

    Article  PubMed  CAS  Google Scholar 

  42. Mikkelsen, J. H., Runager, K. & Andersen, C. B. F. The human protein haptoglobin inhibits IsdH-mediated heme-sequestering by Staphylococcus aureus. J. Biol. Chem. 295, 1781–1791 (2020).

    Article  PubMed  CAS  Google Scholar 

  43. Saederup, K. L. et al. The Staphylococcus aureus protein IsdH inhibits host hemoglobin scavenging to promote heme acquisition by the pathogen. J. Biol. Chem. 291, 23989–23998 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Ochsner, U. A., Johnson, Z. & Vasil, M. L. Genetics and regulation of two distinct haem-uptake systems, phu and has, in Pseudomonas aeruginosa. Microbiology 146, 185–198 (2000).

    Article  PubMed  CAS  Google Scholar 

  45. Bateman, T. J. et al. A Slam-dependent hemophore contributes to heme acquisition in the bacterial pathogen Acinetobacter baumannii. Nat. Commun. 12, 6270 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Rivera-Chavez, F. & Mekalanos, J. J. Cholera toxin promotes pathogen acquisition of host-derived nutrients. Nature 572, 244–248 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Hider, R. C. & Kong, X. Chemistry and biology of siderophores. Nat. Prod. Rep. 27, 637–657 (2010).

    Article  PubMed  CAS  Google Scholar 

  48. Sheldon, J. R., Laakso, H. A. & Heinrichs, D. E. Iron acquisition strategies of bacterial pathogens. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.VMBF-0010-2015 (2016).

    Article  PubMed  Google Scholar 

  49. Miethke, M. & Marahiel, M. A. Siderophore-based iron acquisition and pathogen control. Microbiol. Mol. Biol. Rev. 71, 413–451 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Schalk, I. J. & Guillon, L. Fate of ferrisiderophores after import across bacterial outer membranes: different iron release strategies are observed in the cytoplasm or periplasm depending on the siderophore pathways. Amino Acids 44, 1267–1277 (2013).

    Article  PubMed  CAS  Google Scholar 

  51. Perry, W. J. et al. Staphylococcus aureus exhibits heterogeneous siderophore production within the vertebrate host. Proc. Natl Acad. Sci. USA 116, 21980–21982 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Beasley, F. C., Marolda, C. L., Cheung, J., Buac, S. & Heinrichs, D. E. Staphylococcus aureus transporters Hts, Sir, and Sst capture iron liberated from human transferrin by Staphyloferrin A, Staphyloferrin B, and catecholamine stress hormones, respectively, and contribute to virulence. Infect. Immun. 79, 2345–2355 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Beasley, F. C. et al. Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus. Mol. Microbiol. 72, 947–963 (2009).

    Article  PubMed  CAS  Google Scholar 

  54. Sheldon, J. R. & Heinrichs, D. E. Recent developments in understanding the iron acquisition strategies of Gram positive pathogens. FEMS Microbiol. Rev. 39, 592–630 (2015).

    Article  PubMed  Google Scholar 

  55. Sheldon, J. R., Marolda, C. L. & Heinrichs, D. E. TCA cycle activity in Staphylococcus aureus is essential for iron-regulated synthesis of staphyloferrin A, but not staphyloferrin B: the benefit of a second citrate synthase. Mol. Microbiol. 92, 824–839 (2014).

    Article  PubMed  CAS  Google Scholar 

  56. Sheldon, J. R. & Skaar, E. P. Acinetobacter baumannii can use multiple siderophores for iron acquisition, but only acinetobactin is required for virulence. PLoS Pathog. 16, e1008995 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Pletzer, D., Braun, Y. & Weingart, H. Swarming motility is modulated by expression of the putative xenosiderophore transporter SppR-SppABCD in Pseudomonas aeruginosa PA14. Antonie Van. Leeuwenhoek 109, 737–753 (2016).

    Article  PubMed  CAS  Google Scholar 

  58. Xu, F., Zeng, X., Haigh, R. D., Ketley, J. M. & Lin, J. Identification and characterization of a new ferric enterobactin receptor, CfrB, in Campylobacter. J. Bacteriol. 192, 4425–4435 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Ellermann, M. & Arthur, J. C. Siderophore-mediated iron acquisition and modulation of host–bacterial interactions. Free Radic. Biol. Med. 105, 68–78 (2017).

    Article  PubMed  CAS  Google Scholar 

  60. Perraud, Q. et al. Opportunistic use of catecholamine neurotransmitters as siderophores to access iron by Pseudomonas aeruginosa. Environ. Microbiol. 24, 878–893 (2022).

    Article  PubMed  CAS  Google Scholar 

  61. Correnti, C. & Strong, R. K. Mammalian siderophores, siderophore-binding lipocalins, and the labile iron pool. J. Biol. Chem. 287, 13524–13531 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Zsila, F. & Beke-Somfai, T. Human host-defense peptide LL-37 targets stealth siderophores. Biochem. Biophys. Res. Commun. 526, 780–785 (2020).

    Article  PubMed  CAS  Google Scholar 

  63. Lau, C. K., Krewulak, K. D. & Vogel, H. J. Bacterial ferrous iron transport: the Feo system. FEMS Microbiol. Rev. 40, 273–298 (2016).

    Article  PubMed  CAS  Google Scholar 

  64. Sestok, A. E., Linkous, R. O. & Smith, A. T. Toward a mechanistic understanding of Feo-mediated ferrous iron uptake. Metallomics 10, 887–898 (2018).

    Article  PubMed  CAS  Google Scholar 

  65. Costa, L. F. et al. Iron acquisition pathways and colonization of the inflamed intestine by Salmonella enterica serovar Typhimurium. Int. J. Med. Microbiol. 306, 604–610 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Minandri, F. et al. Role of iron uptake systems in Pseudomonas aeruginosa virulence and airway infection. Infect. Immun. 84, 2324–2335 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Runci, F. et al. Contribution of active iron uptake to Acinetobacter baumannii pathogenicity. Infect. Immun. https://doi.org/10.1128/IAI.00755-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Subashchandrabose, S. et al. Acinetobacter baumannii genes required for bacterial survival during bloodstream infection. mSphere https://doi.org/10.1128/mSphere.00013-15 (2016).

    Article  PubMed  Google Scholar 

  69. Nagy, T. A., Moreland, S. M. & Detweiler, C. S. Salmonella acquires ferrous iron from haemophagocytic macrophages. Mol. Microbiol. 93, 1314–1326 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  70. Perez, N., Johnson, R., Sen, B. & Ramakrishnan, G. Two parallel pathways for ferric and ferrous iron acquisition support growth and virulence of the intracellular pathogen Francisella tularensis Schu S4. Microbiologyopen 5, 453–468 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Bearden, S. W., Staggs, T. M. & Perry, R. D. An ABC transporter system of Yersinia pestis allows utilization of chelated iron by Escherichia coli SAB11. J. Bacteriol. 180, 1135–1147 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Grass, G. et al. FieF (YiiP) from Escherichia coli mediates decreased cellular accumulation of iron and relieves iron stress. Arch. Microbiol. 183, 9–18 (2005).

    Article  PubMed  CAS  Google Scholar 

  73. Katoh, H., Hagino, N., Grossman, A. R. & Ogawa, T. Genes essential to iron transport in the cyanobacterium Synechocystis sp. strain PCC 6803. J. Bacteriol. 183, 2779–2784 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Cao, J., Woodhall, M. R., Alvarez, J., Cartron, M. L. & Andrews, S. C. EfeUOB (YcdNOB) is a tripartite, acid-induced and CpxAR-regulated, low-pH Fe2+ transporter that is cryptic in Escherichia coli K-12 but functional in E. coli O157:H7. Mol. Microbiol. 65, 857–875 (2007).

    Article  PubMed  CAS  Google Scholar 

  75. Grosse, C. et al. A new ferrous iron-uptake transporter, EfeU (YcdN), from Escherichia coli. Mol. Microbiol. 62, 120–131 (2006).

    Article  PubMed  CAS  Google Scholar 

  76. Kammler, M., Schon, C. & Hantke, K. Characterization of the ferrous iron uptake system of Escherichia coli. J. Bacteriol. 175, 6212–6219 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Christenson, E. T. et al. The iron-regulated vacuolar Legionella pneumophila MavN protein is a transition-metal transporter. Proc. Natl Acad. Sci. USA 116, 17775–17785 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Isaac, D. T., Laguna, R. K., Valtz, N. & Isberg, R. R. MavN is a Legionella pneumophila vacuole-associated protein required for efficient iron acquisition during intracellular growth. Proc. Natl Acad. Sci. USA 112, E5208–E5217 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Andreini, C., Banci, L., Bertini, I. & Rosato, A. Zinc through the three domains of life. J. Proteome Res. 5, 3173–3178 (2006).

    Article  PubMed  CAS  Google Scholar 

  80. Rahman, M. T. & Karim, M. M. Metallothionein: a potential link in the regulation of zinc in nutritional immunity. Biol. Trace Elem. Res. 182, 1–13 (2018).

    Article  PubMed  CAS  Google Scholar 

  81. Juttukonda, L. J. & Skaar, E. P. Manganese homeostasis and utilization in pathogenic bacteria. Mol. Microbiol. 97, 216–228 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Kambe, T., Tsuji, T., Hashimoto, A. & Itsumura, N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol. Rev. 95, 749–784 (2015).

    Article  PubMed  CAS  Google Scholar 

  83. Kozlyuk, N. et al. S100 proteins in the innate immune response to pathogens. Methods Mol. Biol. 1929, 275–290 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Zackular, J. P., Chazin, W. J. & Skaar, E. P. Nutritional immunity: S100 proteins at the host–pathogen interface. J. Biol. Chem. 290, 18991–18998 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Nakashige, T. G., Zygiel, E. M., Drennan, C. L. & Nolan, E. M. Nickel sequestration by the host-defense protein human calprotectin. J. Am. Chem. Soc. 139, 8828–8836 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Nakashige, T. G., Zhang, B., Krebs, C. & Nolan, E. M. Human calprotectin is an iron-sequestering host-defense protein. Nat. Chem. Biol. 11, 765–771 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Willers, M. et al. S100A8 and S100A9 are important for postnatal development of gut microbiota and immune system in mice and infants. Gastroenterology 159, 2130–2145.e5 (2020).

    Article  PubMed  CAS  Google Scholar 

  89. Buchau, A. S. et al. S100A15, an antimicrobial protein of the skin: regulation by E. coli through Toll-like receptor 4. J. Invest. Dermatol. 127, 2596–2604 (2007).

    Article  PubMed  CAS  Google Scholar 

  90. Glaser, R. et al. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat. Immunol. 6, 57–64 (2005).

    Article  PubMed  CAS  Google Scholar 

  91. Lee, K. C. & Eckert, R. L. S100A7 (psoriasin) — mechanism of antibacterial action in wounds. J. Invest. Dermatol. 127, 945–957 (2007).

    Article  PubMed  CAS  Google Scholar 

  92. Dow, A. et al. Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis. PLoS Pathog. 17, e1009570 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Hesse, L. E., Lonergan, Z. R., Beavers, W. N. & Skaar, E. P. The Acinetobacter baumannii Znu system overcomes host-imposed nutrient zinc limitation. Infect. Immun. https://doi.org/10.1128/IAI.00746-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Liu, Y. et al. Magnesium sensing regulates intestinal colonization of enterohemorrhagic Escherichia coli O157:H7. mBio https://doi.org/10.1128/mBio.02470-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Quan, G., Xia, P., Lian, S., Wu, Y. & Zhu, G. Zinc uptake system ZnuACB is essential for maintaining pathogenic phenotype of F4ac+ enterotoxigenic E. coli (ETEC) under a zinc restricted environment. Vet. Res. 51, 127 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Zackular, J. P. et al. ZupT facilitates Clostridioides difficile resistance to host-mediated nutritional immunity. mSphere https://doi.org/10.1128/mSphere.00061-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ganguly, T., Peterson, A. M., Kajfasz, J. K., Abranches, J. & Lemos, J. A. Zinc import mediated by AdcABC is critical for colonization of the dental biofilm by Streptococcus mutans in an animal model. Mol. Oral. Microbiol. 36, 214–224 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Hohle, T. H., Franck, W. L., Stacey, G. & O’Brian, M. R. Bacterial outer membrane channel for divalent metal ion acquisition. Proc. Natl Acad. Sci. USA 108, 15390–15395 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  100. Mortensen, B. L., Rathi, S., Chazin, W. J. & Skaar, E. P. Acinetobacter baumannii response to host-mediated zinc limitation requires the transcriptional regulator Zur. J. Bacteriol. 196, 2616–2626 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Calmettes, C. et al. The molecular mechanism of Zinc acquisition by the neisserial outer-membrane transporter ZnuD. Nat. Commun. 6, 7996 (2015).

    Article  PubMed  CAS  Google Scholar 

  102. Kumar, P., Sannigrahi, S. & Tzeng, Y. L. The Neisseria meningitidis ZnuD zinc receptor contributes to interactions with epithelial cells and supports heme utilization when expressed in Escherichia coli. Infect. Immun. 80, 657–667 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Dashper, S. G. et al. A novel Porphyromonas gingivalis FeoB plays a role in manganese accumulation. J. Biol. Chem. 280, 28095–28102 (2005).

    Article  PubMed  CAS  Google Scholar 

  104. Bersch, B. et al. New insights into histidine triad proteins: solution structure of a Streptococcus pneumoniae PhtD domain and zinc transfer to AdcAII. PLoS ONE 8, e81168 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Graham, A. I. et al. Severe zinc depletion of Escherichia coli: roles for high affinity zinc binding by ZinT, zinc transport and zinc-independent proteins. J. Biol. Chem. 284, 18377–18389 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Ilari, A. et al. The Salmonella enterica ZinT structure, zinc affinity and interaction with the high-affinity uptake protein ZnuA provide insight into the management of periplasmic zinc. Biochim. Biophys. Acta 1840, 535–544 (2014).

    Article  PubMed  CAS  Google Scholar 

  107. Kehl-Fie, T. E. & Skaar, E. P. Nutritional immunity beyond iron: a role for manganese and zinc. Curr. Opin. Chem. Biol. 14, 218–224 (2010).

    Article  PubMed  CAS  Google Scholar 

  108. Petrarca, P., Ammendola, S., Pasquali, P. & Battistoni, A. The Zur-regulated ZinT protein is an auxiliary component of the high-affinity ZnuABC zinc transporter that facilitates metal recruitment during severe zinc shortage. J. Bacteriol. 192, 1553–1564 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Cerasi, M. et al. The ZupT transporter plays an important role in zinc homeostasis and contributes to Salmonella enterica virulence. Metallomics 6, 845–853 (2014).

    Article  PubMed  CAS  Google Scholar 

  110. Grass, G., Wong, M. D., Rosen, B. P., Smith, R. L. & Rensing, C. ZupT is a Zn(II) uptake system in Escherichia coli. J. Bacteriol. 184, 864–866 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Sabri, M., Houle, S. & Dozois, C. M. Roles of the extraintestinal pathogenic Escherichia coli ZnuACB and ZupT zinc transporters during urinary tract infection. Infect. Immun. 77, 1155–1164 (2009).

    Article  PubMed  CAS  Google Scholar 

  112. Corbett, D. et al. Two zinc uptake systems contribute to the full virulence of Listeria monocytogenes during growth in vitro and in vivo. Infect. Immun. 80, 14–21 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Rosadini, C. V., Gawronski, J. D., Raimunda, D., Arguello, J. M. & Akerley, B. J. A novel zinc binding system, ZevAB, is critical for survival of nontypeable Haemophilus influenzae in a murine lung infection model. Infect. Immun. 79, 3366–3376 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Bobrov, A. G. et al. The Yersinia pestis siderophore, yersiniabactin, and the ZnuABC system both contribute to zinc acquisition and the development of lethal septicaemic plague in mice. Mol. Microbiol. 93, 759–775 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Braud, A., Geoffroy, V., Hoegy, F., Mislin, G. L. & Schalk, I. J. Presence of the siderophores pyoverdine and pyochelin in the extracellular medium reduces toxic metal accumulation in Pseudomonas aeruginosa and increases bacterial metal tolerance. Environ. Microbiol. Rep. 2, 419–425 (2010).

    Article  PubMed  CAS  Google Scholar 

  116. Braud, A., Hoegy, F., Jezequel, K., Lebeau, T. & Schalk, I. J. New insights into the metal specificity of the Pseudomonas aeruginosa pyoverdine–iron uptake pathway. Environ. Microbiol. 11, 1079–1091 (2009).

    Article  PubMed  CAS  Google Scholar 

  117. Chaturvedi, K. S., Hung, C. S., Crowley, J. R., Stapleton, A. E. & Henderson, J. P. The siderophore yersiniabactin binds copper to protect pathogens during infection. Nat. Chem. Biol. 8, 731–736 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Kobayashi, S. et al. Micacocidin A, B and C, novel antimycoplasma agents from Pseudomonas sp. II. Structure elucidation. J. Antibiot. 51, 328–332 (1998).

    Article  CAS  Google Scholar 

  119. Kreutzer, M. F. et al. Biosynthesis of a complex yersiniabactin-like natural product via the mic locus in phytopathogen Ralstonia solanacearum. Appl. Environ. Microbiol. 77, 6117–6124 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Price, S. L. et al. Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2104073118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Behnsen, J. et al. Siderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut. Nat. Commun. 12, 7016 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Zhao, B. et al. Structural analysis of cytochrome P450 105N1 involved in the biosynthesis of the zincophore, coelibactin. Int. J. Mol. Sci. 13, 8500–8513 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ghssein, G. et al. Biosynthesis of a broad-spectrum nicotianamine-like metallophore in Staphylococcus aureus. Science 352, 1105–1109 (2016).

    Article  PubMed  CAS  Google Scholar 

  124. Grim, K. P. et al. The metallophore staphylopine enables Staphylococcus aureus to compete with the host for zinc and overcome nutritional immunity. mBio https://doi.org/10.1128/mBio.01281-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Citiulo, F. et al. Candida albicans scavenges host zinc via Pra1 during endothelial invasion. PLoS Pathog. 8, e1002777 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Cortese, M. S. et al. Metal chelating properties of pyridine-2,6-bis(thiocarboxylic acid) produced by Pseudomonas spp. and the biological activities of the formed complexes. Biometals 15, 103–120 (2002).

    Article  PubMed  CAS  Google Scholar 

  127. Leach, L. H., Morris, J. C. & Lewis, T. A. The role of the siderophore pyridine-2,6-bis(thiocarboxylic acid) (PDTC) in zinc utilization by Pseudomonas putida DSM 3601. Biometals 20, 717–726 (2007).

    Article  PubMed  CAS  Google Scholar 

  128. Jean, S., Juneau, R. A., Criss, A. K. & Cornelissen, C. N. Neisseria gonorrhoeae evades calprotectin-mediated nutritional immunity and survives neutrophil extracellular traps by production of TdfH. Infect. Immun. 84, 2982–2994 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Maurakis, S. et al. The novel interaction between Neisseria gonorrhoeae TdfJ and human S100A7 allows gonococci to subvert host zinc restriction. PLoS Pathog. 15, e1007937 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Stork, M. et al. Zinc piracy as a mechanism of Neisseria meningitidis for evasion of nutritional immunity. PLoS Pathog. 9, e1003733 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Stork, M. et al. An outer membrane receptor of Neisseria meningitidis involved in zinc acquisition with vaccine potential. PLoS Pathog. 6, e1000969 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Wang, T. et al. Type VI secretion system transports Zn2+ to combat multiple stresses and host immunity. PLoS Pathog. 11, e1005020 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Wang, T. et al. ZntR positively regulates T6SS4 expression in Yersinia pseudotuberculosis. J. Microbiol. 55, 448–456 (2017).

    Article  PubMed  CAS  Google Scholar 

  134. Si, M. et al. Manganese scavenging and oxidative stress response mediated by type VI secretion system in Burkholderia thailandensis. Proc. Natl Acad. Sci. USA 114, E2233–E2242 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Lonergan, Z. R. et al. An Acinetobacter baumannii, zinc-regulated peptidase maintains cell wall integrity during immune-mediated nutrient sequestration. Cell Rep. 26, 2009–2018.e6 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Kim, N. et al. The role of Zur-regulated lipoprotein A in bacterial morphology, antimicrobial susceptibility, and production of outer membrane vesicles in Acinetobacter baumannii. BMC Microbiol. 21, 27 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Murphy, S. G. et al. Endopeptidase regulation as a novel function of the zur-dependent zinc starvation response. mBio https://doi.org/10.1128/mBio.02620-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Pishchany, G., Dickey, S. E. & Skaar, E. P. Subcellular localization of the Staphylococcus aureus heme iron transport components IsdA and IsdB. Infect. Immun. 77, 2624–2634 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Haas, C. E. et al. A subset of the diverse COG0523 family of putative metal chaperones is linked to zinc homeostasis in all kingdoms of life. BMC Genomics 10, 470 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Jordan, M. R. et al. Mechanistic insights into the metal-dependent activation of Zn(II)-dependent metallochaperones. Inorg. Chem. 58, 13661–13672 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Blaby-Haas, C. E., Flood, J. A., Crecy-Lagard, V. & Zamble, D. B. YeiR: a metal-binding GTPase from Escherichia coli involved in metal homeostasis. Metallomics 4, 488–497 (2012).

    Article  PubMed  CAS  Google Scholar 

  143. Chandrangsu, P., Huang, X., Gaballa, A. & Helmann, J. D. Bacillus subtilis FolE is sustained by the ZagA zinc metallochaperone and the alarmone ZTP under conditions of zinc deficiency. Mol. Microbiol. 112, 751–765 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Sousa Geros, A., Simmons, A., Drakesmith, H., Aulicino, A. & Frost, J. N. The battle for iron in enteric infections. Immunology 161, 186–199 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Martin, J. E. et al. A Mn-sensing riboswitch activates expression of a Mn2+/Ca2+ ATPase transporter in Streptococcus. Nucleic Acids Res. 47, 6885–6899 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Knippel, R. J. et al. Clostridioides difficile senses and hijacks host heme for incorporation into an oxidative stress defense system. Cell Host Microbe 28, 411–421.e6 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Knippel, R. J. et al. Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection. PLoS Pathog. 14, e1007486 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Saillant, V. et al. A novel Enterococcus faecalis heme transport regulator (FhtR) senses host heme to control its intracellular homeostasis. mBio https://doi.org/10.1128/mBio.03392-20 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Hodgkinson, V. & Petris, M. J. Copper homeostasis at the host–pathogen interface. J. Biol. Chem. 287, 13549–13555 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Giachino, A. & Waldron, K. J. Copper tolerance in bacteria requires the activation of multiple accessory pathways. Mol. Microbiol. 114, 377–390 (2020).

    Article  PubMed  CAS  Google Scholar 

  151. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Tan, G. et al. Copper binding in IscA inhibits iron–sulphur cluster assembly in Escherichia coli. Mol. Microbiol. 93, 629–644 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Macomber, L., Rensing, C. & Imlay, J. A. Intracellular copper does not catalyze the formation of oxidative DNA damage in Escherichia coli. J. Bacteriol. 189, 1616–1626 (2007).

    Article  PubMed  CAS  Google Scholar 

  155. Tree, J. J., Kidd, S. P., Jennings, M. P. & McEwan, A. G. Copper sensitivity of CueO mutants of Escherichia coli K-12 and the biochemical suppression of this phenotype. Biochem. Biophys. Res. Commun. 328, 1205–1210 (2005).

    Article  PubMed  CAS  Google Scholar 

  156. Grass, G. et al. Linkage between catecholate siderophores and the multicopper oxidase CueO in Escherichia coli. J. Bacteriol. 186, 5826–5833 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Li, C., Li, Y. & Ding, C. The role of copper homeostasis at the host–pathogen axis: from bacteria to fungi. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20010175 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Sitthisak, S., Knutsson, L., Webb, J. W. & Jayaswal, R. K. Molecular characterization of the copper transport system in Staphylococcus aureus. Microbiology 153, 4274–4283 (2007).

    Article  PubMed  CAS  Google Scholar 

  159. Fu, Y., Chang, F. M. & Giedroc, D. P. Copper transport and trafficking at the host–bacterial pathogen interface. Acc. Chem. Res. 47, 3605–3613 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Fu, Y. et al. A new structural paradigm in copper resistance in Streptococcus pneumoniae. Nat. Chem. Biol. 9, 177–183 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Gold, B. et al. Identification of a copper-binding metallothionein in pathogenic mycobacteria. Nat. Chem. Biol. 4, 609–616 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Franke, S., Grass, G., Rensing, C. & Nies, D. H. Molecular analysis of the copper-transporting efflux system CusCFBA of Escherichia coli. J. Bacteriol. 185, 3804–3812 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Katumba, G. L., Tran, H. & Henderson, J. P. The Yersinia high-pathogenicity island encodes a siderophore-dependent copper response system in uropathogenic Escherichia coli. mBio https://doi.org/10.1128/mBio.02391-21 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Barth, V. C. et al. Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2022136118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Ladomersky, E. & Petris, M. J. Copper tolerance and virulence in bacteria. Metallomics 7, 957–964 (2015).

    Article  PubMed  CAS  Google Scholar 

  166. Sullivan, M. J., Goh, K. G. K. & Ulett, G. C. Cellular management of zinc in group B Streptococcus supports bacterial resistance against metal intoxication and promotes disseminated infection. mSphere https://doi.org/10.1128/mSphere.00105-21 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Botella, H. et al. Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe 10, 248–259 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Martin, J. E. et al. The zinc efflux activator SczA protects Streptococcus pneumoniae serotype 2 D39 from intracellular zinc toxicity. Mol. Microbiol. 104, 636–651 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Ong, C. L., Gillen, C. M., Barnett, T. C., Walker, M. J. & McEwan, A. G. An antimicrobial role for zinc in innate immune defense against group A Streptococcus. J. Infect. Dis. 209, 1500–1508 (2014).

    Article  PubMed  CAS  Google Scholar 

  170. Ong, C. Y., Berking, O., Walker, M. J. & McEwan, A. G. New insights into the role of zinc acquisition and zinc tolerance in group A streptococcal infection. Infect. Immun. https://doi.org/10.1128/IAI.00048-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Johnson, M. D., Kehl-Fie, T. E. & Rosch, J. W. Copper intoxication inhibits aerobic nucleotide synthesis in Streptococcus pneumoniae. Metallomics 7, 786–794 (2015).

    Article  PubMed  CAS  Google Scholar 

  172. Stocks, C. J. et al. Frontline science: LPS-inducible SLC30A1 drives human macrophage-mediated zinc toxicity against intracellular Escherichia coli. J. Leukoc. Biol. 109, 287–297 (2021).

    Article  PubMed  CAS  Google Scholar 

  173. Stojiljkovic, I. & Perkins-Balding, D. Processing of heme and heme-containing proteins by bacteria. DNA Cell Biol. 21, 281–295 (2002).

    Article  PubMed  CAS  Google Scholar 

  174. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Li, J. et al. Zinc toxicity and iron–sulfur cluster biogenesis in Escherichia coli. Appl. Environ. Microbiol. https://doi.org/10.1128/AEM.01967-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Lonergan, Z. R. & Skaar, E. P. Nutrient zinc at the host–pathogen interface. Trends Biochem. Sci. 44, 1041–1056 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. 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).

    Article  PubMed  CAS  Google Scholar 

  179. Zhanel, G. G. et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs 79, 271–289 (2019).

    Article  PubMed  CAS  Google Scholar 

  180. Hijazi, S. et al. Antimicrobial activity of gallium compounds on ESKAPE pathogens. Front. Cell Infect. Microbiol. 8, 316 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Greenwald, J. et al. Real time fluorescent resonance energy transfer visualization of ferric pyoverdine uptake in Pseudomonas aeruginosa. A role for ferrous iron. J. Biol. Chem. 282, 2987–2995 (2007).

    Article  PubMed  CAS  Google Scholar 

  182. Elbourne, A. et al. Antibacterial liquid metals: biofilm treatment via magnetic activation. ACS Nano 14, 802–817 (2020).

    Article  PubMed  CAS  Google Scholar 

  183. Shin, M. et al. Characterization of an antibacterial agent targeting ferrous iron transport protein FeoB against Staphylococcus aureus and Gram-positive bacteria. ACS Chem. Biol. 16, 136–149 (2021).

    Article  PubMed  CAS  Google Scholar 

  184. Shin, M. et al. Identification of a new antimicrobial agent against bovine mastitis-causing Staphylococcus aureus. J. Agric. Food Chem. 69, 9968–9978 (2021).

    Article  PubMed  CAS  Google Scholar 

  185. Veloria, J. et al. Developing colorimetric and luminescence-based high-throughput screening platforms for monitoring the GTPase activity of ferrous iron transport protein B (FeoB). SLAS Discov. 24, 597–605 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Bennett, M. R. et al. Human mAbs to Staphylococcus aureus IsdA provide protection through both heme-blocking and Fc-mediated mechanisms. J. Infect. Dis. 219, 1264–1273 (2019).

    Article  PubMed  CAS  Google Scholar 

  187. Kim, H. K. et al. IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge. Vaccine 28, 6382–6392 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Qamsari, M. M., Rasooli, I., Chaudhuri, S., Astaneh, S. D. A. & Schryvers, A. B. Hybrid antigens expressing surface loops of ZnuD from Acinetobacter baumannii is capable of inducing protection against infection. Front. Immunol. 11, 158 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Bruhn, K. W. & Spellberg, B. Transferrin-mediated iron sequestration as a novel therapy for bacterial and fungal infections. Curr. Opin. Microbiol. 27, 57–61 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Lin, L. et al. Transferrin iron starvation therapy for lethal bacterial and fungal infections. J. Infect. Dis. 210, 254–264 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Pi, H. & Helmann, J. D. Sequential induction of Fur-regulated genes in response to iron limitation in Bacillus subtilis. Proc. Natl Acad. Sci. USA 114, 12785–12790 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Potter, A. D. et al. Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection. Proc. Natl Acad. Sci. USA 117, 12394–12401 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Frank, M. W. et al. Host fatty acid utilization by Staphylococcus aureus at the infection site. mBio https://doi.org/10.1128/mBio.00920-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Pandey, A. K. & Sassetti, C. M. Mycobacterial persistence requires the utilization of host cholesterol. Proc. Natl Acad. Sci. USA 105, 4376–4380 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Pal, R. R. et al. Pathogenic E. coli extracts nutrients from infected host cells utilizing injectisome components. Cell 177, 683–696.e18 (2019).

    Article  PubMed  CAS  Google Scholar 

  198. Grant, C. R. et al. Distinct gene clusters drive formation of ferrosome organelles in bacteria. Nature https://doi.org/10.1038/s41586-022-04741-x (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Weinberg, E. D. Iron availability and infection. Biochim. Biophys. Acta 1790, 600–605 (2009).

    Article  PubMed  CAS  Google Scholar 

  200. Ampel, N. M., Van Wyck, D. B., Aguirre, M. L., Willis, D. G. & Popp, R. A. Resistance to infection in murine β-thalassemia. Infect. Immun. 57, 1011–1017 (1989).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Wanachiwanawin, W. Infections in E-β thalassemia. J. Pediatr. Hematol. Oncol. 22, 581–587 (2000).

    Article  PubMed  CAS  Google Scholar 

  202. Quenee, L. E. et al. Hereditary hemochromatosis restores the virulence of plague vaccine strains. J. Infect. Dis. 206, 1050–1058 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Wright, A. C., Simpson, L. M. & Oliver, J. D. Role of iron in the pathogenesis of Vibrio vulnificus infections. Infect. Immun. 34, 503–507 (1981).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Sanchez, K. K. et al. Cooperative metabolic adaptations in the host can favor asymptomatic infection and select for attenuated virulence in an enteric pathogen. Cell 175, 146–158.e15 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Zackular, J. P. et al. Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection. Nat. Med. 22, 1330–1334 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Melby, K., Slordahl, S., Gutteberg, T. J. & Nordbo, S. A. Septicaemia due to Yersinia enterocolitica after oral overdoses of iron. Br. Med. J. 285, 467–468 (1982).

    Article  CAS  Google Scholar 

  207. Okhuysen, P. C. & Dupont, H. L. Enteroaggregative Escherichia coli (EAEC): a cause of acute and persistent diarrhea of worldwide importance. J. Infect. Dis. 202, 503–505 (2010).

    Article  PubMed  Google Scholar 

  208. Xue, Y., Osborn, J., Panchal, A. & Mellies, J. L. The RpoE stress response pathway mediates reduction of the virulence of enteropathogenic Escherichia coli by zinc. Appl. Environ. Microbiol. 81, 3766–3774 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Liu, M. J. et al. ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB. Cell Rep. 3, 386–400 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Hall, S. C. et al. Critical role of zinc transporter (ZIP8) in myeloid innate immune cell function and the host response against bacterial pneumonia. J. Immunol. 207, 1357–1370 (2021).

    Article  PubMed  CAS  Google Scholar 

  211. Jones, D. G. & Suttle, N. F. The effect of copper deficiency on the resistance of mice to infection with Pasteurella haemolytica. J. Comp. Pathol. 93, 143–149 (1983).

    Article  PubMed  CAS  Google Scholar 

  212. Newberne, P. M., Hunt, C. E. & Young, V. R. The role of diet and the reticuloendothelial system in the response of rats to Salmonella typhilmurium infection. Br. J. Exp. Pathol. 49, 448–457 (1968).

    PubMed  PubMed Central  CAS  Google Scholar 

  213. Juttukonda, L. J. et al. Dietary manganese promotes staphylococcal infection of the heart. Cell Host Microbe 22, 531–542.e8 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors thank the members of the Skaar laboratory for critical reading of this manuscript. The writing of this manuscript was supported through fellowships to C.C.M. through the National Institutes of Health (NIH) (F32GM142246) and research grants to E.P.S. (R01, AI150702, R01 AI073843, R01AI101171, R01AI138581, R01AI145992).

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Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Caitlin C. Murdoch & Eric P. Skaar

  2. Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University School of Medicine, Nashville, TN, USA

    Caitlin C. Murdoch & Eric P. Skaar

  3. Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN, USA

    Eric P. Skaar

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  1. Caitlin C. Murdoch
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  2. Eric P. Skaar
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Contributions

C.C.M. researched data for the article. E.P.S. and C.C.M contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Eric P. Skaar.

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Nature Reviews Microbiology thanks Mark O’Brian, Isabelle Schalk and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Mis-metalation

The association of metalloproteins with non-cognate metals, often abrogating enzymatic function.

Siderophore

A secreted low molecular-weight molecule that binds and sequesters iron (Fe), and potentially other metals.

Ferritin

An intracellular protein used in the storage of labile cellular iron (Fe).

Haptoglobin

A host protein that binds haemoglobin in circulation, preventing oxidative activity and use by pathogens.

Haemopexin

(HPX). A host serum protein that binds circulating haem with high affinity.

Biliverdin

A green pigmented by-product of haem catabolism by haem oxygenases.

Staphylobilin

A by-product of haem catabolism by IsdG family haem oxygenases.

Superoxide dismutase

An enzyme that catalyses the formation of hydrogen peroxide from superoxide.

EF-hand motif

A helix–loop–helix calcium binding structural domain present in S100 proteins.

G3E family P-loop GTPases

A conserved family of proteins that bind and hydrolyse GTP with known roles in bacterial metallocentre biosynthesis.

COG0523 proteins

A subgroup of G3E P-loop GTPase proteins predicted to function as metallochaperones.

Riboswitch

A regulatory RNA segment that binds metals and modulates expression of the full transcript.

Fe–S clusters

Inorganic redox-active protein cofactors that play structural and functional roles in metalloproteins formed by complexes of iron (Fe) and sulfides.

P-type family ATPases

A class of autocatalytic ATP-hydrolysing transporters found across all kingdoms of life.

Metallothioneins

Low molecular-weight cysteine-rich proteins that bind metals such as zinc (Zn), copper (Cu) and cadmium.

Phosphoglucomutase

An enzyme that catalyses the transfer of phosphate between the C1 and C6 positions on glucose monomers.

RND-family transporters

Gram-negative bacterial efflux transporters that span the inner and outer membrane and use the proton gradient to move substrates from the cytosol to the extracellular space.

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Murdoch, C.C., Skaar, E.P. Nutritional immunity: the battle for nutrient metals at the host–pathogen interface. Nat Rev Microbiol 20, 657–670 (2022). https://doi.org/10.1038/s41579-022-00745-6

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