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@ARTICLE{Schtt:646213,
      author       = {Schütt, Isabell and Einwohlt, Philip and Wandinger,
                      Anna-Maria and Teuffel, Jonathan and Wirsing, Regina and
                      Hlawatschke, Ben H. and Fehlauer, Hanna L. and Bothe,
                      Sebastian and Bader, Nicole and Monaci, Emanuele and
                      Kreikemeyer, Bernd and Schindelin, Hermann and Wade, Rebecca
                      C. and Fiedler, Tomas},
      title        = {{I}nhibitors of {G}ap{N}-dependent {NADPH} supply as
                      potential lead compounds for novel therapeutics against
                      {S}treptococcus pyogenes},
      journal      = {Virulence},
      volume       = {17},
      number       = {1},
      issn         = {2150-5594},
      address      = {Austin, Tex.},
      publisher    = {Landes Bioscience},
      reportid     = {PUBDB-2026-00758},
      pages        = {2609393},
      year         = {2026},
      abstract     = {Infections with Streptococcus pyogenes are among the most
                      important diseases caused by bacteria and are responsible
                      for around 500,000 deaths every year. In 2024,
                      macrolide-resistant S. pyogenes was added to the WHO’s
                      list of priority pathogens. The non-phosphorylating
                      glyceraldehyde-3-phosphate dehydrogenase GapN has been
                      identified as a potential drug target in S. pyogenes.
                      SpyGapN is the major NADP-reducing enzyme in these bacteria
                      as they lack the oxidative part of the pentose phosphate
                      pathway. In this study, in silico docking of compound
                      libraries to the glyceraldehyde 3-phosphate binding pocket
                      of SpyGapN was used to screen for potential competitive
                      inhibitors. Among the candidates identified with this
                      approach, 1,2-dihydroxyethane-1,2-disulfonate (glyoxal
                      bisulfite) showed the strongest inhibition of SpyGapN
                      activity in vitro. In a complementary approach,
                      crystallographic fragment screening was conducted, which
                      identified the ultra-low-molecular-weight compounds
                      pyrimidine-5-amine and 4-hydroxypyridazine targeting the
                      cofactor-binding pocket of SpyGapN. Both
                      low-molecular-weight compounds were experimentally confirmed
                      to inhibit the activity of purified SpyGapN. Combinations of
                      glyoxal bisulfite with either pyrimidine-5-amine or
                      4-hydroxypyridazine enhanced the inhibitory effect of
                      SpyGapN. Glyoxal bisulfite was able to kill S. pyogenes.
                      This effect was accelerated by combining glyoxal bisulfite
                      with 4-hydroxypyridazine. While these findings suggest that
                      inhibition of SpyGapN probably contributes to the observed
                      antibacterial activity, the exact mechanism of action
                      remains to be confirmed, as the compounds also affect other
                      G3P-converting enzymes. Nevertheless, these compounds
                      provide a promising starting point for the development of
                      more specific SpyGapN inhibitors.},
      cin          = {EMBL-User},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P13-20150101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1080/21505594.2025.2609393},
      url          = {https://bib-pubdb1.desy.de/record/646213},
}