Network Medicine

Blueprint for antimicrobial hit discovery targeting metabolic networks

Proceedings of the National Academy of Sciences of the United States of America 10.1073, 1-6 (2010) 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.


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J. Park, D. S. Lee, N. A. Christakis, A.-L. Barabási

Molecular Systems Biology 5:262, 1-7 (2009)

V. Vermeirssen, M. Inmaculada Barrasa, C. Hidalgo, J.-A. B. Babon, R. Sequerra, L. Doucette-Stamm, A.-L. Barabási, A. J.M. Walhout

Genome Research 17, 061-1071 (2007)

D.-S. Lee, J. Park, K. A. Kay, N. A. Christakis, Z. N. Oltvai, A.-L. Barabási

Proceedings of the National Academy of Sciences 105, 9880-9885 (2008)