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

Denis Kazakiewicz, Jonathan R. Karr, Karol M. Langner, Dariusz Plewczynski

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Pages (from-to)91-97
Number of pages7
JournalComputational Biology and Chemistry
StatePublished - Dec 2015


  • Drug repositioning
  • Homology modeling
  • Metabolic modeling
  • Mycoplasma genitalium
  • Systems biology
  • Thymidylate kinase


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