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Mathematical models of biochemical networks form a cornerstone of bacterial systems biology. Inconsistencies between simulation output and experimental data point to gaps in knowledge about the fundamental biology of the organism. One such inconsistency centers on the gene  aldA  in  Escherichia coli : it is essential in a computational model of  E. coli  metabolism, but experimentally it is not. Here, we reconcile this disparity by providing evidence that  aldA  and  prpC  form a synthetic lethal pair, as the double knockout could only be created through complementation with a plasmid-borne copy of  aldA . Moreover, virtual and biological screening against the two proteins led to a set of compounds that inhibited the growth of  E. coli  and  Salmonella enterica  serovar Typhimurium synergistically at 100–200 μM individual concentrations. These results highlight the power of metabolic models to drive basic biological discovery and their potential use to discover new combination antibiotics.

frontiers in microbiology

Model-driven discovery of synergistic inhibitors against E. coli and S. enterica serovar Typhimurium targeting a novel synthetic lethal pair, aldA and prpC