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@ARTICLE{LpezPrez:904334,
      author       = {López-Pérez, Arancha and Freischem, Stefan and Grimm,
                      Immanuel and Weiergräber, Oliver and Dingley, Andrew and
                      López-Alberca, María and Waldmann, Herbert and Vollmer,
                      Waldemar and Kumar, Kamal and Vuong, Cuong},
      title        = {{D}iscovery of {P}yrrolidine-2,3-diones as {N}ovel
                      {I}nhibitors of {P}. aeruginosa {PBP}3},
      journal      = {Antibiotics},
      volume       = {10},
      number       = {5},
      issn         = {2079-6382},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2021-05904},
      pages        = {529 -},
      year         = {2021},
      abstract     = {The alarming threat of the spread of multidrug resistant
                      bacteria currently leaves clinicians with very limited
                      options to combat infections, especially those from
                      Gram-negative bacteria. Hence, innovative strategies to
                      deliver the next generation of antibacterials are urgently
                      needed. Penicillin binding proteins (PBPs) are proven
                      targets inhibited by β-lactam antibiotics. To discover
                      novel, non-β-lactam inhibitors against PBP3 of Pseudomonas
                      aeruginosa, we optimised a fluorescence assay based on a
                      well-known thioester artificial substrate and performed a
                      target screening using a focused protease-targeted library
                      of 2455 compounds, which led to the identification of
                      pyrrolidine-2,3-dione as a potential scaffold to inhibit the
                      PBP3 target. Further chemical optimisation using a one-pot
                      three-component reaction protocol delivered compounds with
                      excellent target inhibition, initial antibacterial
                      activities against P. aeruginosa and no apparent
                      cytotoxicity. Our investigation revealed the key structural
                      features; for instance, 3-hydroxyl group (R2) and a
                      heteroaryl group (R1) appended to the N-pyrroldine-2,3-dione
                      via methylene linker required for target inhibition.
                      Overall, the discovery of the pyrrolidine-2,3-dione class of
                      inhibitors of PBP3 brings opportunities to target
                      multidrug-resistant bacterial strains and calls for further
                      optimisation to improve antibacterial activity against P.
                      aeruginosa},
      cin          = {IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {34064358},
      UT           = {WOS:000653463000001},
      doi          = {10.3390/antibiotics10050529},
      url          = {https://juser.fz-juelich.de/record/904334},
}