Salmonella target list for drug targeting

List of primers for constructing deletions of all genes can be found here.

To identify candidate proteins for drug targeting we examined data from several different sources, summarized in this table. A brief description of each column is provided:

1. STMID : Salmonella ORF identifier
2. Name : Given gene name for protein
3. Function : Annotation
4. FIGID : Identifier from the FIG database
5. FIG Functional Group : functional group assignment in FIG
6. Conserved in all pathogens : flag indicating if the gene was conserved in all 5 pathogens examined; Escherichia coli E22, Escherichia coli O157:H7 (EHEC), Shigella flexneri 2a str. 2457T, Vibrio cholerae 1587 and Yersinia enterocolitica 8081
7. Conserved in all pathogens not in Eukaryotes : flag indicating if the gene was conserved in pathogens (above) but not in Homo sapiens, Mus musculus or Rattus norvegicus
8. SIEVE Score : score for prediction of type III secretion by SIEVE
9. %GC : the percentage G+C content of the gene
10. PID similarity to E. coli protein : the percentage sequence identity of the protein to the best hit in E. coli k12
11. PID similarity to Mus musculus : the percentage sequence identity of the protein to the best hit in M. musculus
12. Essential for virulence in STM : the gene was found on N of five negative genetic screens for virulence in Salmonella (Chan et al., 2005; Lawley et al., 2006; Morgan et al., 2004; Shah et al., 2005).
13. STMEssential : found to be essential for Salmonella growth [future]
14. ECOEssentiality : is an E. coli homolog of this gene essential for growth
15. ECOEssBin : Unused
16. VirTarget : does this meet criteria for a virulence-associated target (conserved in pathogens, not in eukaryotes, and essential for virulence in Salmonella)
17. HomologVirEss : has a homolog in another pathogen been identified as being essential for virulence
18. Structure : the PDB identifier for a known, or closely related, structure

Here is text describing this process

"Computational identification and ranking of potential therapeutic targets To provide a list of potential therapeutic targets we used a comparative genomics approach to combine several different sources of data. The NMPDR database (McNeil et al., 2007) was used to obtain a list of homologs (determined using the bi-directional best hit method) for Salmonella 14028 genes in the following pathogens: Escherichia coli E22, Escherichia coli O157:H7 (EHEC), Shigella flexneri 2a str. 2457T, Vibrio cholerae 1587 and Yersinia enterocolitica 8081; as well as the following mammals: Homo sapiens, Mus musculus and Rattus norvegicus. We identified 2456 genes that had homologs in all pathogens examined, and 1449 of these had no homologs in the mammals listed above. We removed genes that were known to be essential for viability from the list as they cannot be deleted. The 1237 genes identified represent our core list of most interesting targets several of which have already been shown to be associated with virulence in at least one of the pathogens listed above. The reason that “associated” is used rather than shown is because they were identified in negative selection experiments, which are not very accurate. We found that 173 genes from this list are associated with virulence based on negative selection experiments in Salmonella (Chan et al., 2005; Lawley et al., 2006; Morgan et al., 2004; Shah et al., 2005). Of our core list of 1237 genes, 375 genes encode proteins with determined structures or with homologs with determined structures (p<e-50). This core list represents a starting point for further analysis and development of therapeutic drugs. These results can be accessed at http://www.sysbep.org/data/CompletePrimerDesign_02_02_2009.html. To provide a list of the most interesting candidates we examined the 1237 core genes for virulence in the other pathogens using previously published in vivo negative selection experiments carried out in APEC (Li et al., 2005), EHEC (Dziva et al., 2004), UHEC (Bahrani-Mougeot et al., 2002), C. rhodentium (Mundy et al., 2003), V. cholerae (Chiang and Mekalanos, 1998) and Y. pestis (Darwin, 2005). We found 13 genes that were associated with virulence in at least two of these organisms including Salmonella (see table). Although only a fraction of the genes have been carefully tested this result is certainly encouraging. Interestingly, we found biotin synthase, bioB, on this list, which we have previously shown to be important for growth inside macrophages (Shi, et al. manuscript submitted)."