1. Blueprint for antimicrobial hit discovery targeting metabolic networks
- Author
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Shen, Y., Liu, J., Estiu, G., Isin, B., Ahn, Y-Y., Lee, D-S., Barabasi, A-L., Kapatral, V., Wiest, O., and Oltvai, Z.N.
- Subjects
Anti-infective agents -- Product development ,Drug therapy, Combination -- Research ,Drug targeting -- Research ,Pharmaceutical research -- Innovations ,Science and technology - Abstract
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. antibiotics | flux balance analysis | virtual screening doi/10.1073/pnas.0909181107
- Published
- 2010