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Robust Salmonella metabolism limits possibilities for new antimicrobials

Nature volume 440, pages 303–307 (2006)Cite this article

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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Figure 1: Overview of Salmonella metabolism during typhoid fever.
Figure 2: Experimental strategy for in vivo Salmonella proteomics.
Figure 3: Properties of Salmonella metabolic enzymes during typhoid fever.

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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

  1. Daniel Becker, Matthias Selbach and Claudia Rollenhagen: *These authors contributed equally to this work

Authors and 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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  1. Daniel Becker
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Correspondence to Dirk Bumann.

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Supplementary information

Supplementary Figure 1

Overview of Salmonella metabolism in a mouse enteritis model. (PDF 57 kb)

Supplementary Table 1

Published Salmonella mutant phenotypes in typhoid fever models. (XLS 24 kb)

Supplementary Table 2

Salmonella genes that are non-functional in serovars causing systemic disease. (XLS 23 kb)

Supplementary Table 3

Summary of functional and proteome evidence for Salmonella metabolic enzymes and pathways in typhoid fever and enteritis models. (XLS 68 kb)

Supplementary Table 4

Salmonella genes with controversial in vitro phenotypes. (XLS 18 kb)

Supplementary Table 5

Salmonella proteome data for typhoid fever and enteritis models. (XLS 168 kb)

Supplementary Table 6

Growth rates of Salmonella mutants in typhoid fever and enteritis models. (XLS 52 kb)

Supplementary Table 7

Metabolites likely to be present in Salmonella during typhoid fever and/or enteritis. (XLS 57 kb)

Supplementary Table 8

Properties of Salmonella enzymes representing potential antimicrobial targets. (XLS 57 kb)

Supplementary Table 9

Salmonella nutrition during typhoid fever and enteritis. (XLS 31 kb)

Supplementary Methods

Technical details of experimental methods used in this study. (DOC 50 kb)

Supplementary Notes

This file contains additional references. (DOC 55 kb)

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Becker, D., Selbach, M., Rollenhagen, C. et al. Robust Salmonella metabolism limits possibilities for new antimicrobials. Nature 440, 303–307 (2006). https://doi.org/10.1038/nature04616

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