Blueprint for antimicrobial hit discovery targeting metabolic networks.
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.
Shen
Y
Y
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Liu
J
J
Estiu
G
G
Isin
B
B
Ahn
Y-Y
YY
Lee
D-S
DS
Barabási
A-L
AL
Kapatral
V
V
Wiest
O
O
Oltvai
Z N
ZN
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
D000900:Anti-Bacterial Agents; D005227:Fatty Acids