A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium.
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.
Center for Innovative Research, Medical University of Biaƚystok, Biaƚystok 15-089, Poland; Center for Statistics, Universiteit Hasselt, Hasselt BE3500, Belgium; Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt BE3500, Belgium.
Denis
D
Kazakiewicz
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate Program in Biophysics, Stanford University, Stanford, CA 94305, USA.
Jonathan R
JR
Karr
Department of Molecular Physiology & Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
Karol M
KM
Langner
Center for Innovative Research, Medical University of Biaƚystok, Biaƚystok 15-089, Poland; Centre of New Technologies, University of Warsaw, Warsaw 02-097, Poland; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
Dariusz
D
Plewczynski
D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D058492:Drug Repositioning / Q000379:methods*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D045704:Mycoplasma genitalium / Q000187:drug effects* / Q000201:enzymology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D049490:Systems Biology; D013941:Thymine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D010880:Piperidines; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013941:Thymine
Drug repositioning; Homology modeling; Metabolic modeling; Mycoplasma genitalium; Systems biology; Thymidylate kinase