Integrative genome-scale metabolic analysis of Vibrio vulnificus for drug targeting and discovery.
Although the genomes of many microbial pathogens have been studied to help identify effective drug targets and novel drugs, such efforts have not yet reached full fruition. In this study, we report a systems biological approach that efficiently utilizes genomic information for drug targeting and discovery, and apply this approach to the opportunistic pathogen Vibrio vulnificus CMCP6. First, we partially re-sequenced and fully re-annotated the V. vulnificus CMCP6 genome, and accordingly reconstructed its genome-scale metabolic network, VvuMBEL943. The validated network model was employed to systematically predict drug targets using the concept of metabolite essentiality, along with additional filtering criteria. Target genes encoding enzymes that interact with the five essential metabolites finally selected were experimentally validated. These five essential metabolites are critical to the survival of the cell, and hence were used to guide the cost-effective selection of chemical analogs, which were then screened for antimicrobial activity in a whole-cell assay. This approach is expected to help fill the existing gap between genomics and drug discovery.
Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 program), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Hyun Uk
HU
Kim
Soo Young
SY
Kim
Haeyoung
H
Jeong
Tae Yong
TY
Kim
Jae Jong
JJ
Kim
Hyon E
HE
Choy
Kyu Yang
KY
Yi
Joon Haeng
JH
Rhee
Sang Yup
SY
Lee
D016000:Cluster Analysis; D055808:Drug Discovery / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics; D016680:Genome, Bacterial; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055442:Metabolome / Q000235:genetics*; D055432:Metabolomics / Q000379:methods*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010802:Phylogeny; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D041261:Vibrio vulnificus / Q000235:genetics* / Q000378:metabolism*
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