期刊
FRONTIERS IN MICROBIOLOGY
卷 6, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2015.00958
关键词
synthetic lethality; antibiotic development; drug discovery; systems biology; metabolic reconstruction; bacterial metabolism; model-based drug target discovery; pathway gap filling
类别
资金
- NIH/NIGMS [GM098105]
- [GM057089]
- NNF Center for Biosustainability [New Bioactive Compounds] Funding Source: researchfish
- Novo Nordisk Fonden [NNF10CC1016517] Funding Source: researchfish
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 colt: 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. colt and Salmonella enterica serovar Typhimurium synergistically at 100-200 mu M individual concentrations. These results highlight the power of metabolic models to drive basic biological discovery and their potential use to discover new combination antibiotics.
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