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The siderophore yersiniabactin binds copper to protect pathogens during infection

Nature Chemical Biology volume 8, pages 731–736 (2012)Cite this article

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Abstract

Bacterial pathogens secrete chemically diverse iron chelators called siderophores, which may exert additional distinctive functions in vivo. Among these, uropathogenic Escherichia coli often coexpress the virulence-associated siderophore yersiniabactin (Ybt) with catecholate siderophores. Here we used a new MS screening approach to reveal that Ybt is also a physiologically favorable Cu(II) ligand. Direct MS detection of the resulting Cu(II)–Ybt complex in mice and humans with E. coli urinary tract infections demonstrates copper binding to be a physiologically relevant in vivo interaction during infection. Ybt expression corresponded to higher copper resistance among human urinary tract isolates, suggesting a protective role for this interaction. Chemical and genetic characterization showed that Ybt helps bacteria resist copper toxicity by sequestering host-derived Cu(II) and preventing its catechol-mediated reduction to Cu(I). Together, these studies reveal a new virulence-associated function for Ybt that is distinct from iron binding.

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Figure 1: A Ybt neutral loss screen reveals formation of a new Cu(II)–Ybt complex in human urine.
Figure 2: Cupric Ybt is produced in cystitis patients infected with Ybt-producing strains.
Figure 3: Ybt promotes E. coli growth in copper-toxic conditions.
Figure 4: Catecholate siderophores and Ybt exert opposing effects on copper cytotoxicity.

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Acknowledgements

We would like to thank M. Gross, H. Rohrs and Y. Zhang for high-resolution MS analysis and J. Pinker for assistance with small-molecule purification. We are grateful to S. Hultgren, G. Marshall and B. Ford for helpful discussions. J.P.H. holds a Career Award for Medical Scientists from the Burroughs-Wellcome Fund. We additionally acknowledge US National Institutes of Health grants K12 HD001459-09, AI 07172-24, P30 HL101263-01, P50 DK64540, U01 DK082315 and UL1 RR024992. MS was supported by P41-RR00954, 8-P41 GM103422-35 (NCRR), P60-DK20579 and P30-DK56341.

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Authors and Affiliations

  1. Center for Women′s Infectious Diseases Research, Washington University School of Medicine, St. Louis, Missouri, USA

    Kaveri S Chaturvedi, Chia S Hung & Jeffrey P Henderson

  2. Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, USA

    Kaveri S Chaturvedi, Chia S Hung & Jeffrey P Henderson

  3. Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Kaveri S Chaturvedi, Chia S Hung, Jan R Crowley & Jeffrey P Henderson

  4. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA

    Ann E Stapleton

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Contributions

K.S.C. and J.P.H. conceived and designed the experiments. K.S.C., C.S.H. and J.R.C. performed the experiments. A.E.S. collected human specimens. K.S.C., C.S.H. and J.P.H. analyzed the data. K.S.C. and J.P.H. wrote the paper.

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Correspondence to Jeffrey P Henderson.

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Chaturvedi, K., Hung, C., Crowley, J. et al. The siderophore yersiniabactin binds copper to protect pathogens during infection. Nat Chem Biol 8, 731–736 (2012). https://doi.org/10.1038/nchembio.1020

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