title: Steps toward broad-spectrum therapeutics: discovering virulence-associated genes present in diverse human pathogens.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM, USA. stubben@lanl.gov
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Stubben
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Duffield
authors.forename: Ian A
authors.initials: IA
authors.lastname: Cooper
authors.forename: Donna C
authors.initials: DC
authors.lastname: Ford
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gans
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Karlyshev
authors.forename: Bryan
authors.initials: B
authors.lastname: Lingard
authors.forename: Petra C F
authors.initials: PC
authors.lastname: Oyston
authors.forename: Anna
authors.initials: A
authors.lastname: de Rochefort
authors.forename: Jian
authors.initials: J
authors.lastname: Song
authors.forename: Brendan W
authors.initials: BW
authors.lastname: Wren
authors.forename: Rick W
authors.initials: RW
authors.lastname: Titball
authors.forename: Murray
authors.initials: M
authors.lastname: Wolinsky
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial; D023281:Genomics; D006801:Humans; D014774:Virulence / Q000187:drug effects* / Q000235:genetics*; D015011:Yersinia pseudotuberculosis / Q000235:genetics / Q000472:pathogenicity
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins