A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2

Abstract

Background: Metabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. Salmonella enterica subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem.

Results: Here, we describe a community-driven effort, in which more than 20 experts in S. Typhimurium biology and systems biology collaborated to reconcile and expand the S. Typhimurium BiGG knowledge-base. The consensus MR was obtained starting from two independently developed MRs for S. Typhimurium. Key results of this reconstruction jamboree include i) development and implementation of a community-based workflow for MR annotation and reconciliation; ii) incorporation of thermodynamic information; and iii) use of the consensus MR to identify potential multi-target drug therapy approaches.

Conclusion: Taken together, with the growing number of parallel MRs a structured, community-driven approach will be necessary to maximize quality while increasing adoption of MRs in experimental design and interpretation.

Figure 1

Approach to reconcile two metabolic reconstructions (MR). This figure illustrates the automated comparison tool developed for the Salmonella reconstruction jamboree. Both MRs are translated into a common language (based on KEGG [44]). Metabolites and reactions that could not be mapped onto KEGG were subject to manual evaluation by the jamboree team. The overlapping part of the MRs was directly moved into the consensus MR while reactions and metabolites unique to a MR were evaluated manually. This approach can be readily applied to comparison of any two MRs.

Figure 2

Candidate drug targets. The figure contains all predicted synthetic lethal interactions for STM_v1.0 in LB medium. A line connecting two genes represents a synthetic lethal pair. A group of genes surrounded by a dashed box represents a protein complex requiring all enclosed elements to function. Yellow background means associated with sulfur metabolism. Blue background indicates that the synthetic lethal pairs are functional homolog's. Red gene means that there is a chemical known to inhibit the gene-product in STM_v1.0.