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@ARTICLE{Porta:864929,
      author       = {Porta, Nicola and Zaschke-Kriesche, Julia and Frieg,
                      Benedikt and Gopalswamy, Mohanraj and Zivkovic, Aleksandra
                      and Etzkorn, Manuel and Stark, Holger and Smits, Sander H.
                      J. and Gohlke, Holger},
      title        = {{S}mall-molecule inhibitors of nisin resistance protein
                      {NSR} from the human pathogen {S}treptococcus agalactiae},
      journal      = {Bioorganic $\&$ medicinal chemistry},
      volume       = {27},
      number       = {20},
      issn         = {0968-0896},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2019-04532},
      pages        = {115079},
      year         = {2019},
      abstract     = {Lantibiotics are antimicrobial peptides produced by
                      Gram-positive bacteria and active in the nanomolar range.
                      Nisin is the most intensely studied and used lantibiotic,
                      with applications as food preservative and recognized
                      potential for clinical usage. However, different bacteria
                      that are pathogenic for humans and do not produce nisin,
                      including Streptococcus agalactiae, show an innate
                      resistance that has been related to the nisin resistance
                      protein (NSR), a membrane-associated protease. Here, we
                      report the first-in-class small-molecule inhibitors of SaNSR
                      identified by virtual screening based on a previously
                      derived structural model of the nisin/NSR complex. The
                      inhibitors belong to three different chemotypes, of which
                      the halogenated phenyl-urea derivative NPG9 is the most
                      potent one. Co-administration of NPG9 with nisin yields
                      increased potency compared to nisin alone in
                      SaNSR-expressing bacteria. The binding mode of NPG9,
                      predicted with molecular docking and validated by extensive
                      molecular dynamics simulations, confirms a
                      structure-activity relationship derived from the in vivo
                      data. Saturation transfer difference-NMR experiments
                      demonstrate direct binding of NPG9 to SaNSR and agree with
                      the predicted binding mode. Our results demonstrate the
                      potential to overcome SaNSR-related lantibiotic resistance
                      by small molecules.},
      cin          = {JSC / NIC / ICS-6},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / 553 - Physical Basis of Diseases (POF3-553) /
                      Forschergruppe Gohlke $(hkf7_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / G:(DE-HGF)POF3-553 /
                      $G:(DE-Juel1)hkf7_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31500943},
      UT           = {WOS:000486383500014},
      doi          = {10.1016/j.bmc.2019.115079},
      url          = {https://juser.fz-juelich.de/record/864929},
}