Predicting conserved essential genes in bacteria: in silico identification of putative drug targets.
Many genes have been listed as putatively essential for bacterial viability in the Database of Essential Genomes (DEG), although few have been experimentally validated. By prioritising targets according to the criteria suggested by the Research and Training in Tropical Diseases (TDR) Targets database, we have developed a modified down-selection tool to identify essential genes conserved across diverse genera. Using this approach we identified 52 proteins conserved to 7 or more of the 14 genomes in DEG. We confirmed the validity of the down-selection by attempting to make mutants of 8 of these targets in a model organism, Yersinia pseudotuberculosis, which is not closely related to any of the bacteria in DEG. Mutants were recovered for only one of the 8 targets, suggesting that the other 7 were essential in Y. pseudotuberculosis, an impressive success rate compared to other approaches of identification for such targets. Identification of essential proteins common in diverse bacterial genera can then be used to facilitate the selection of effective targets for novel broad-spectrum antibiotics.
Duffield
Melanie
M
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. mlduffield@dstl.gov.uk
Cooper
Ian
I
McAlister
Erin
E
Bayliss
Marc
M
Ford
Donna
D
Oyston
Petra
P
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000166:cytology / Q000187:drug effects / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015169:Colony Count, Microbial; D019295:Computational Biology / Q000379:methods*; D017124:Conserved Sequence / Q000235:genetics*; D005798:Genes, Bacterial / Q000235:genetics*; D020043:Genes, Essential / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D015203:Reproducibility of Results
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins