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A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium

Paper ID Volume ID Publish Year Pages File Format Full-Text
15034 1368 2015 7 PDF Available
Title
A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium
Abstract

•We combined systems and structural modeling to repurpose antibiotics for new hosts.•We applied our novel approach to the infectious bacterium Mycoplasma genitalium.•Our method suggests that thymidylate kinase is a good potential drug target.•Our method suggests that piperidinylthymines are good potential lead compounds.•Combined systems and structural modeling is a powerful tool for drug repositioning.

Bacteria are increasingly resistant to existing antibiotics, which target a narrow range of pathways. New methods are needed to identify targets, including repositioning targets among distantly related species. We developed a novel combination of systems and structural modeling and bioinformatics to reposition known antibiotics and targets to new species. We applied this approach to Mycoplasma genitalium, a common cause of urethritis. First, we used quantitative metabolic modeling to identify enzymes whose expression affects the cellular growth rate. Second, we searched the literature for inhibitors of homologs of the most fragile enzymes. Next, we used sequence alignment to assess that the binding site is shared by M. genitalium, but not by humans. Lastly, we used molecular docking to verify that the reported inhibitors preferentially interact with M. genitalium proteins over their human homologs. Thymidylate kinase was the top predicted target and piperidinylthymines were the top compounds. Further work is needed to experimentally validate piperidinylthymines. In summary, combined systems and structural modeling is a powerful tool for drug repositioning.

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Keywords
Systems biology; Metabolic modeling; Homology modeling; Drug repositioning; Mycoplasma genitalium; Thymidylate kinase
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A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 59, Part B, December 2015, Pages 91–97
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us