Blueprint for antimicrobial hit discovery targeting metabolic networks
Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-01, Vol.107 (3), p.1082-1087 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 107 |
| creator | Shen, Y Liu, J Estiu, G Isin, B Ahn, Y.Y Lee, D.S Barabási, A.L Kapatral, V Wiest, O Oltvai, Z.N |
| description | Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy. |
| doi_str_mv | 10.1073/pnas.0909181107 |
| format | Article |
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| subjects | Active sites Anti-Bacterial Agents - pharmacology Antibiotics Antimicrobials Biological Sciences Cells Drug Discovery E coli Enzymes Escherichia coli Escherichia coli - drug effects Escherichia coli - metabolism Fatty Acids - biosynthesis Genomes Genomics Metabolic diseases Metabolism Models, Molecular Molecules Staphylococcus aureus - drug effects Staphylococcus aureus - metabolism Yeast |
| title | Blueprint for antimicrobial hit discovery targeting metabolic networks |
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