Metabolite-centric approaches for the discovery of antibacterials using genome-scale metabolic networks.
Development of genome-scale metabolic models and various constraints-based flux analyses have enabled more sophisticated examination of metabolism. Recently reported metabolite essentiality studies are also based on the constraints-based modeling, but approaches metabolism from a metabolite-centric perspective, providing synthetic lethal combination of reactions and clues for the rational discovery of antibacterials. In this study, metabolite essentiality analysis was applied to the genome-scale metabolic models of four microorganisms: Escherichia coli, Helicobacter pylori, Mycobacterium tuberculosis and Staphylococcus aureus. Furthermore, chokepoints, metabolites surrounded by enzymes that uniquely consume and/or produce them, were also calculated based on the network properties of the above organisms. A systematic drug targeting strategy was developed by combining information from these two methods. Final drug target metabolites are presented and examined with knowledge from the literature.
Kim
Tae Yong
TY
Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering, BioProcess Engineering Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Kim
Hyun Uk
HU
Lee
Sang Yup
SY
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D055808:Drug Discovery; D004926:Escherichia coli / Q000378:metabolism; D016680:Genome, Bacterial / Q000235:genetics / Q000502:physiology*; D016480:Helicobacter pylori / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins