Steps toward broad-spectrum therapeutics: discovering virulence-associated genes present in diverse human pathogens.
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.
Stubben
Chris J
CJ
Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM, USA. stubben@lanl.gov
Duffield
Melanie L
ML
Cooper
Ian A
IA
Ford
Donna C
DC
Gans
Jason D
JD
Karlyshev
Andrey V
AV
Lingard
Bryan
B
Oyston
Petra C F
PC
de Rochefort
Anna
A
Song
Jian
J
Wren
Brendan W
BW
Titball
Rick W
RW
Wolinsky
Murray
M
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
D000890:Anti-Infective Agents; D001426:Bacterial Proteins