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Molecular basis for resistance to silver cations in Salmonella


Here we report the genetic and proposed molecular basis for silver resistance in pathogenic microorganisms. The silver resistance determinant from a hospital burn ward Salmonella plasmid contains nine open reading frames, arranged in three measured and divergently transcribed RNAs. The resistance determinant encodes a periplasmic silver–specific binding protein (SilE) plus apparently two parallel efflux pumps: one, a P–type ATPase (SilP); the other, a membrane potential–dependent three–polypeptide cation/proton antiporter (SilCBA). The sil determinant is governed by a two–component membrane sensor and transcriptional responder comprising silS and silR, which are co–transcribed. The availability of the sil silver–resistance determinant will be the basis for mechanistic molecular and biochemical studies as well as molecular epidemiology of silver resistance in clinical settings in which silver is used as a biocide.

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Figure 1: Silver resistance determinant, genes, transcripts and protein products.
Figure 2: The metal–binding protein SilE.
Figure 3: Transcript analysis of the silver resistance determinant.
Figure 4: Primer extension analysis of RNA.


  1. Gupta, A. & Silver, S. Silver as a biocide: will resistance become a problem? Nature Biotechnol. 16, 888 (1998).

    Article  CAS  Google Scholar 

  2. Silver, S., Gupta, A. Matsui, K. & Lo, J.–F. Resistance to Ag(I) cations in bacteria: environments, genes and proteins. Metal Based Drugs (in the press).

  3. George, N., Faoagali, J. & Muller, M. SilvazineTM (silver sulfadiazine and chlorhexidine) activity against 200 clinical isolates. Burns 23, 493–495 (1997).

    Article  CAS  Google Scholar 

  4. Modak, S. M., Sampath, L. & Fox, C.L. Jr. Combined topical use of silver sulfadiazine and antibiotics as a possible solution to bacterial resistance in burn wounds. J. Burn Care Rehabil. 9, 359– 363 (1988).

    Article  CAS  Google Scholar 

  5. Pruitt, B.A. Jr., McManus, A.T., Kim, S.H. & Goodwin, C.W. Burn wound infections: current status. World J. Surg. 22, 135–145 (1998).

    Article  Google Scholar 

  6. Chu, C.S., McManus, A.T., Matylevich, N.P., Mason, A.D. Jr, & Pruitt, B.A. Jr. Enhanced survival of autoepidermal–allodermal composite grafts in allosensitized animals by use of silver nylon dressings and direct current. J. Trauma 39, 273–278 (1995) .

    Article  CAS  Google Scholar 

  7. Sampath, L.A., Chowdhury, N., Caraos, L. & Modak, S.M. Infection resistance of surface modified catheters with either short–lived or prolonged activity. J. Hosp. Infect. 30, 201–210 (1995).

    Article  CAS  Google Scholar 

  8. Greenfeld, J.I. et al. Decreased bacterial adherence and biofilm formation on chlorhexidine and silver sulfadiazine–impregnated central venous catheters implanted in swine. Crit. Care Med. 23, 894– 900 (1995).

    Article  CAS  Google Scholar 

  9. Gabriel, M.M., Mayo, M.S., May, L.L., Simmons, R.B. & Ahearn, D.G. In vitro evaluation of the efficacy of a silver–coated catheter. Curr. Microbiol. 33, 1– 5 (1996).

    Article  CAS  Google Scholar 

  10. McHugh, S.L., Moellering, R.C., Hopkins, C.C. & Swartz, M.N. Salmonella typhimurium resistant to silver nitrate, chloramphenicol, and ampicillin. Lancet i, 235– 240 (1975).

    Article  Google Scholar 

  11. Annear, D.I., Mee, B.J. & Bailey, M. Instability and linkage of silver resistance, lactose fermentation and colony structure in Enterobacter cloacae. J. Clin. Path. 29, 441–443 (1976).

    Article  CAS  Google Scholar 

  12. Bridges, K., Kidson, A., Lowbury, E.J.L. & Wilkins, M.D. Gentamicin– and silver–resistant Pseudomonas. Brit. Med. J. 1, 446–449 (1979).

    Article  CAS  Google Scholar 

  13. Silver, S. & Phung, L.T. Bacterial heavy metal resistance: new surprises. Annu. Rev. Microbiol. 50, 753–789 (1996).

    Article  CAS  Google Scholar 

  14. Silver, S. Genes for all metals—a bacterial view of the Periodic Table. J. Indust. Microbiol. Biotech. 20, 1– 12 (1998).

    Article  CAS  Google Scholar 

  15. Hobman, J.L. & Brown, N.L. in Metal Ions in Biological Systems Vol. 34 (eds. Sigel, A. & Sigel, H.) 527– 568 (Marcel Dekker, New York, 1997).

    Google Scholar 

  16. Summers, A.O. Untwist and shout: a heavy metal–responsive transcriptional regulator. J. Bacteriol. 174, 3097– 3101 (1992).

    Article  CAS  Google Scholar 

  17. Gupta, A., Maynes, M. & Silver, S. The effects of halides on plasmid silver resistance in Escherichia coli. Appl. Environ. Microbiol. 64, 5042–5045 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Brown, N.L., Barrett, S.R., Camakaris, J., Lee, B.T. O. & Rouch, D.A. Molecular genetics and transport analysis of the copper–resistance determinant (pco) from Escherichia coli plasmid pRJ1004. Mol. Microbiol. 17, 1153–1166 (1995).

    Article  CAS  Google Scholar 

  19. Hoch, J.A. & Silhavy, T.J. (eds.) Two–Component Signal Transduction (ASM, Washington, DC, 1995).

    Book  Google Scholar 

  20. Rouch, D.A. & Brown, N.L. Copper–inducible transcriptional regulation at two promoters in the Escherichia coli copper resistance determinant pco. Microbiology 143, 1191– 1202 (1997).

    Article  CAS  Google Scholar 

  21. Blattner, F.R. et al. The complete genome sequence of Escherichia coli K–12. Science 277, 1453–1474 (1997).

    Article  CAS  Google Scholar 

  22. Rudd, K.E. Linkage map of Escherichia coli K–12, Edition 10: The physical map. Microbiol. Mol. Biol. Rev. 62, 985– 1019 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. van der Lelie, D. et al. Two–component regulatory system involved in transcriptional control of heavy– metal homoeostasis in Alcaligenes eutrophus. Mol. Microbiol. 23, 493–503 (1997).

    Article  CAS  Google Scholar 

  24. Nies, D. H. & Silver, S. Ion efflux systems involved in bacterial metal resistances. J. Indust. Microbiol. 14, 186–199 (1995).

    Article  CAS  Google Scholar 

  25. Nies, D. H. The cobalt, zinc, and cadmium efflux system CzcABC from Alcaligenes eutrophus functions as a cation–proton antiporter in Escherichia coli. J. Bacteriol. 177, 2707– 2712 (1995).

    Article  CAS  Google Scholar 

  26. Paulsen, I.T., Park, J.H., Choi, P.S. & Saier, M.H. Jr. A family of gram–negative bacterial outer membrane factors that function in the export of proteins, carbohydrates, drugs and heavy metals from gram–negative bacteria. FEMS Microbiol Lett. 156, 1– 8 (1997).

    Article  CAS  Google Scholar 

  27. Solioz, M. & Vulpe, C. CPx–type ATPASE: a class of P–type ATPASE that pump heavy metals. Trends Biochem. Sci. 21, 237–241 (1996).

    Article  CAS  Google Scholar 

  28. Trenor III, C., Lin, W. & Andrews, N.C. Novel bacterial P–type ATPases with histidine–rich heavy–metal–associated sequences. Biochem. Biophys. Res. Commun. 205, 1644–1650 (1994).

    Article  Google Scholar 

  29. Li, X. Z., Nikaido, H. & Williams, K. E. Silver–resistant mutants of Escherichia coli display active efflux of Ag+ and are deficient in porins. J. Bacteriol. 179, 6127– 6132 (1997).

    Article  CAS  Google Scholar 

  30. Solioz, M. & Odermatt, A. Copper and silver transport by CopB–ATPase in membrane vesicles of Enterococcus hirae. J. Biol. Chem. 270, 9217–9221 (1995).

    Article  CAS  Google Scholar 

  31. Ausubel, F.M., et al. (eds.) Current Protocols in Molecular Biology (John Wiley & Sons, New York, 1998).

    Google Scholar 

  32. Rech, S., Wolin, C. & Gunsalus, R.P. Properties of the periplasmic ModA molybdate–binding protein of Escherichia coli. J. Biol. Chem. 271, 2557–2562 (1996).

    Article  CAS  Google Scholar 

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We thank A.O. Summers for the plasmid used in this work and for unpublished data, F. Roberto and P. Goodlove for sequencing and analysis, B.–S.B. Lee for N–terminal polypeptide sequencing and advice, and W. Hendrickson, W. Walden, and D.H. Nies for discussions. This work was supported by a grant from the Department of Energy.

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Correspondence to Amit Gupta.

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Gupta, A., Matsui, K., Lo, JF. et al. Molecular basis for resistance to silver cations in Salmonella. Nat Med 5, 183–188 (1999).

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