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Robust Salmonella metabolism limits possibilities for new antimicrobials

Nature volume 440, pages 303307 (16 March 2006) | Download Citation

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Abstract

New antibiotics are urgently needed to control infectious diseases. Metabolic enzymes could represent attractive targets for such antibiotics, but in vivo target validation is largely lacking. Here we have obtained in vivo information about over 700 Salmonella enterica enzymes from network analysis of mutant phenotypes, genome comparisons and Salmonella proteomes from infected mice. Over 400 of these enzymes are non-essential for Salmonella virulence, reflecting extensive metabolic redundancies and access to surprisingly diverse host nutrients. The essential enzymes identified were almost exclusively associated with a small subgroup of pathways, enabling us to perform a nearly exhaustive screen. Sixty-four enzymes identified as essential in Salmonella are conserved in other important human pathogens, but almost all belong to metabolic pathways that are inhibited by current antibiotics or that have previously been considered for antimicrobial development. Our comprehensive in vivo analysis thus suggests a shortage of new metabolic targets for broad-spectrum antibiotics, and draws attention to some previously known but unexploited targets.

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Acknowledgements

We thank R. Förster for support, T. Aebischer for discussion, M. Sörensen, K. Raba and C. Reimer for technical assistance, and P. Mortensen and J. V. Olsen for providing a script to calibrate the LTQ-FT data. This work was supported by grants from the Deutsche Forschungsgemeinschaft (to D. Bumann).

Author information

Author notes

    • Daniel Becker
    • , Matthias Selbach
    •  & Claudia Rollenhagen

    *These authors contributed equally to this work

Affiliations

  1. Max-Planck-Institute for Infection Biology, Department of Molecular Biology, D-10117 Berlin, Germany

    • Daniel Becker
    • , Claudia Rollenhagen
    • , Thomas F. Meyer
    •  & Dirk Bumann
  2. Max-Planck-Institute of Biochemistry, Department of Proteomics and Signal Transduction, D-82152 Martinsried, Germany

    • Matthias Selbach
    •  & Matthias Mann
  3. Hannover Medical School, Flow Cytometry Core Facility, D-30625 Hannover, Germany

    • Matthias Ballmaier
  4. Hannover Medical School, Institute of Immunology, ‘Mucosal Infections’ Junior Research Group OE 9421, D-30625 Hannover, Germany

    • Dirk Bumann

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Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Dirk Bumann.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Overview of Salmonella metabolism in a mouse enteritis model.

Excel files

  1. 1.

    Supplementary Table 1

    Published Salmonella mutant phenotypes in typhoid fever models.

  2. 2.

    Supplementary Table 2

    Salmonella genes that are non-functional in serovars causing systemic disease.

  3. 3.

    Supplementary Table 3

    Summary of functional and proteome evidence for Salmonella metabolic enzymes and pathways in typhoid fever and enteritis models.

  4. 4.

    Supplementary Table 4

    Salmonella genes with controversial in vitro phenotypes.

  5. 5.

    Supplementary Table 5

    Salmonella proteome data for typhoid fever and enteritis models.

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    Supplementary Table 6

    Growth rates of Salmonella mutants in typhoid fever and enteritis models.

  7. 7.

    Supplementary Table 7

    Metabolites likely to be present in Salmonella during typhoid fever and/or enteritis.

  8. 8.

    Supplementary Table 8

    Properties of Salmonella enzymes representing potential antimicrobial targets.

  9. 9.

    Supplementary Table 9

    Salmonella nutrition during typhoid fever and enteritis.

Word documents

  1. 1.

    Supplementary Methods

    Technical details of experimental methods used in this study.

  2. 2.

    Supplementary Notes

    This file contains additional references.

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DOI

https://doi.org/10.1038/nature04616

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