AUTHOR=Aziz Ramy K., Khaw Valerie , Monk Jonathan M., Brunk Elizabeth , Lewis Robert , Loh Suh I., Mishra Arti , Nagle Amrita A., Satyanarayana Chitkala , Dhakshinamoorthy Saravanakumar , Luche Michele , Kitchen Douglas B., Andrews Kathleen A., Palsson Bernhard O., Charusanti Pep 

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

JOURNAL=Frontiers in Microbiology

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00958

DOI=10.3389/fmicb.2015.00958

ISSN=1664-302X

ABSTRACT=<p>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 <italic>aldA</italic> in <italic>Escherichia coli</italic>: it is essential in a computational model of <italic>E. coli</italic> metabolism, but experimentally it is not. Here, we reconcile this disparity by providing evidence that <italic>aldA</italic> and <italic>prpC</italic> form a synthetic lethal pair, as the double knockout could only be created through complementation with a plasmid-borne copy of <italic>aldA</italic>. Moreover, virtual and biological screening against the two proteins led to a set of compounds that inhibited the growth of <italic>E. coli</italic> and <italic>Salmonella enterica</italic> 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.</p>