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Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative pathogen that uses complex mechanisms to invade and proliferate within mammalian host cells. To investigate possible contributions of metabolic processes to virulence in S. Typhimurium grown under conditions known to induce expression of virulence genes, we used a metabolomics-driven systems biology approach coupled with genome-scale modeling. First, we identified distinct metabolite profiles associated with bacteria grown in either rich or virulence-inducing media and report the most comprehensive coverage of the S. Typhimurium metabolome to date. Second, we applied an omics-informed genome-scale modeling analysis of the functional consequences of adaptive alterations in S. Typhimurium metabolism during growth under our conditions. Modeling efforts highlighted a decreased cellular capability to both produce and utilize intracellular amino acids during stationary phase culture in virulence conditions, despite significant abundance increases for these molecules as observed by our metabolomics measurements. Furthermore, analyses of omics data in the context of the metabolic model indicated rewiring of the metabolic network to support pathways associated with virulence. For example, cellular concentrations of polyamines were perturbed, as well as the predicted capacity for secretion and uptake.

Over the past decade a massive amount of research has been dedicated to generating omics data to gain insight into a variety of biological phenomena, including cancer, obesity, biofuel production, and infection. Although most of these omics data are available publicly, there is a growing concern that much of these data sit in databases without being used or fully analyzed. Statistical inference methods have been widely applied to gain insight into which genes may influence the activities of others in a given omics data set, however, they do not provide information on the underlying mechanisms or whether the interactions are direct or distal. Biochemically, genetically, and genomically consistent knowledge bases are increasingly being used to extract deeper biological knowledge and understanding from these data sets than possible by inferential methods. This improvement is largely due to knowledge bases providing a validated biological context for interpreting the data.