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

doi:10.1186/1471-2164-10-501

BMC Genomics. 2009; 10: 501.

Published online 2009 October 29. doi: 10.1186/1471-2164-10-501

PMCID: PMC2774872

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

Chris J Stubben,^#¹ Melanie L Duffield,^#² Ian A Cooper,² Donna C Ford,² Jason D Gans,¹ Andrey V Karlyshev,³ Bryan Lingard,² Petra CF Oyston,² Anna de Rochefort,² Jian Song,¹ Brendan W Wren,⁴ Rick W Titball,⁵ and Murray Wolinsky¹

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

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

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

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

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

Corresponding author.

^#Contributed equally.

Chris J Stubben: stubben/at/lanl.gov; Melanie L Duffield: mlduffield/at/mail.dstl.gov.uk; Ian A Cooper: iacooper/at/dstl.gov.uk; Donna C Ford: dcford/at/dstl.gov.uk; Jason D Gans: jgans/at/lanl.gov; Andrey V Karlyshev: a.karlyshev/at/kingston.ac.uk; Bryan Lingard: blingard/at/dstl.gov.uk; Petra CF Oyston: pcoyston/at/dstl.gov.uk; Anna de Rochefort: aderochefort/at/dstl.gov.uk; Jian Song: jian/at/lanl.gov; Brendan W Wren: wren/at/lshtm.ac.uk; Rick W Titball: r.w.titball/at/exeter.ac.uk; Murray Wolinsky: murray/at/lanl.gov

Received April 25, 2009; Accepted October 29, 2009.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.

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.

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