Metabolite-centric approaches for the discovery of antibacterials using genome-scale metabolic networks |
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| Authors: | Tae Yong Kim Hyun Uk Kim Sang Yup Lee |
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| Affiliation: | 1. Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 program), BioProcess Engineering Research Center, Korea Advanced Institute of Science and Technology (KAIST), 335 Gwahangno, Yuseong-gu, Daejeon 305-701, Republic of Korea;2. Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, KAIST, 335 Gwahangno, Yuseong-gu, Daejeon 305-701, Republic of Korea;3. Department of Bio and Brain Engineering and Bioinformatics Research Center, KAIST, Daejeon 305-701, Republic of Korea;4. Department of Biological Sciences, KAIST, Daejeon 305-701, Republic of Korea;1. Chemical and Biological Engineering;2. Late Stage Cell Culture, Process R&D Genentech, Inc. 1 DNA Way, MS 32 South San Francisco CA 94080;1. School of Computer Sciences, Tel Aviv University, Tel Aviv 69978, Israel;2. The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;1. CEB-Centre of Biological Engineering, University of Minho, Campus de Gualtar, Braga 4710–057, Portugal;2. Department of Biology and Biological Engineering, Chalmers University of Technology, SE 412 96 Gothenburg, Sweden;1. Department of Biomedical Engineering, Computational Biology, Eindhoven University of Technology, 5612 AZ Eindhoven, the Netherlands;2. Novo Nordisk Foundation Center for Biosustainability at UC San Diego, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA;3. Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA;4. Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA;5. Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA;1. Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea;2. BioInformatics Research Center, KAIST, Daejeon 34141, Republic of Korea;3. BioProcess Engineering Research Center, KAIST, Daejeon 34141, Republic of Korea;4. The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark |
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| 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. |
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