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Open Access Highly Accessed Research article

Steps toward broad-spectrum therapeutics: discovering virulence-associated genes present in diverse human pathogens

Chris J Stubben1, Melanie L Duffield2, Ian A Cooper2, Donna C Ford2, Jason D Gans1, Andrey V Karlyshev3, Bryan Lingard2, Petra CF Oyston2, Anna de Rochefort2, Jian Song1, Brendan W Wren4, Rick W Titball5 and Murray Wolinsky1*

  • * Corresponding author: Murray Wolinsky murray@lanl.gov

  • † Equal contributors

Author Affiliations

1 Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM

2 Biomedical Sciences, Dstl, Porton Down, Salisbury, UK

3 School of Life Sciences, Kingston University, Kingston-upon-Thames, Surrey, UK

4 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

5 School of Biosciences, University of Exeter, Stocker Road, Exeter, UK

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BMC Genomics 2009, 10:501  doi:10.1186/1471-2164-10-501

Published: 29 October 2009

Abstract

Background

New and improved antimicrobial countermeasures are urgently needed to counteract increased resistance to existing antimicrobial treatments and to combat currently untreatable or new emerging infectious diseases. We demonstrate that computational comparative genomics, together with experimental screening, can identify potential generic (i.e., conserved across multiple pathogen species) and novel virulence-associated genes that may serve as targets for broad-spectrum countermeasures.

Results

Using phylogenetic profiles of protein clusters from completed microbial genome sequences, we identified seventeen protein candidates that are common to diverse human pathogens and absent or uncommon in non-pathogens. Mutants of 13 of these candidates were successfully generated in Yersinia pseudotuberculosis and the potential role of the proteins in virulence was assayed in an animal model. Six candidate proteins are suggested to be involved in the virulence of Y. pseudotuberculosis, none of which have previously been implicated in the virulence of Y. pseudotuberculosis and three have no record of involvement in the virulence of any bacteria.

Conclusion

This work demonstrates a strategy for the identification of potential virulence factors that are conserved across a number of human pathogenic bacterial species, confirming the usefulness of this tool.