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

Abstract

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 repositionknown antibiotics and targets to new species. We applied this approach to Mycoplasma genitalium, acommon cause of urethritis. First, we used quantitative metabolic modeling to identify enzymes whoseexpression affects the cellular growth rate. Second, we searched the literature for inhibitors of homologsof the most fragile enzymes. Next, we used sequence alignment to assess that the binding site is shared byM. genitalium, but not by humans. Lastly, we used molecular docking to verify that the reported inhibitorspreferentially interact with M. genitalium proteins over their human homologs. Thymidylate kinase wasthe top predicted target and piperidinylthymines were the top compounds. Further work is needed toexperimentally validate piperidinylthymines. In summary, combined systems and structural modeling isa powerful tool for drug repositioning.