title: Blueprint for antimicrobial hit discovery targeting metabolic networks.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Estiu
authors.forename: B
authors.initials: B
authors.lastname: Isin
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Ahn
authors.forename: D-S
authors.initials: DS
authors.lastname: Lee
authors.forename: A-L
authors.initials: AL
authors.lastname: Barabási
authors.forename: V
authors.initials: V
authors.lastname: Kapatral
authors.forename: O
authors.initials: O
authors.lastname: Wiest
authors.forename: Z N
authors.initials: ZN
authors.lastname: Oltvai
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D055808:Drug Discovery; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D008958:Models, Molecular; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D005227:Fatty Acids