title: Metabolite-centric approaches for the discovery of antibacterials using genome-scale metabolic networks.
abstract: 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.
authors.affiliation: 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.
authors.forename: Tae Yong
authors.initials: TY
authors.lastname: Kim
authors.forename: Hyun Uk
authors.initials: HU
authors.lastname: Kim
authors.forename: Sang Yup
authors.initials: SY
authors.lastname: Lee
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins