Blueprint for antimicrobial hit discovery targeting metabolic networks

被引:87
作者
Shen, Y. [1 ,2 ,3 ]
Liu, J. [2 ,3 ]
Estiu, G. [1 ]
Isin, B. [2 ,3 ]
Ahn, Y-Y. [4 ,5 ,6 ,7 ,8 ]
Lee, D-S. [4 ,5 ,6 ,7 ,8 ]
Barabasi, A-L. [4 ,5 ,6 ,7 ,8 ]
Kapatral, V. [9 ]
Wiest, O. [1 ]
Oltvai, Z. N. [2 ,3 ]
机构
[1] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
[2] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Dept Computat Biol, Pittsburgh, PA 15261 USA
[4] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA
[5] Northeastern Univ, Dept Phys, Boston, MA 02115 USA
[6] Northeastern Univ, Dept Biol, Boston, MA 02115 USA
[7] Northeastern Univ, Dept Comp Sci, Boston, MA 02115 USA
[8] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA
[9] Integrated Genom Inc, Chicago, IL 60612 USA
关键词
antibiotics; flux balance analysis; virtual screening; CARRIER PROTEIN TRANSACYLASE; RESISTANT STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; GENE-EXPRESSION; RECONSTRUCTION; INHIBITOR; GENOMICS; IDENTIFY; FABF;
D O I
10.1073/pnas.0909181107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1082 / 1087
页数:6
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