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Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1082-7. doi: 10.1073/pnas.0909181107. Epub 2010 Jan 5.

Blueprint for antimicrobial hit discovery targeting metabolic networks.

Author information

1
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.

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.

PMID:
20080587
PMCID:
PMC2824290
DOI:
10.1073/pnas.0909181107
[Indexed for MEDLINE]
Free PMC Article

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