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<p>Biofilm formation by <i>Klebsiella pneumoniae</i> is mediated by the type 3 fimbriae Mrk, and regulated by MrkH and 3’,5’-cyclic diguanylic acid (c-di-GMP). We sought to identify specific chemical inhibitors of <i>K. pneumoniae</i> biofilm formation that reduced the activity of MrkH. A compound N-(3-cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2-yl)-2-methoxybenzamide, JT71, reduced <i>K. pneumoniae mrkA</i> promoter activity and biofilm formation by 50% without affecting cell viability. Western blot analysis, hemagglutination assays, electron microscopy and qPCR showed that JT71 reduced type 3 fimbriae production, and transcription of <i>mrkA</i> and <i>mrkH</i>. JT71 demonstrated activity against other clinical and multi-drug resistant <i>K. pneumoniae</i> isolates, and a type 3 fimbriate-positive <i>Citrobacter koseri</i> strain. In silico molecule docking was used to illustrate that JT71 could bind directly to the MrkH protein and block its activity. JT71 possesses promising drug-likeness properties and is non-toxic to mammalian cells. Chemical inhibition of transcriptional regulators that control fimbriae expression can inhibit bacterial biofilm formation.</p>

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Chemical inhibition of MrkH-dependent activation of type 3 fimbriae synthesis and biofilm formation by Klebsiella pneumoniae

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月20日

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  • Jonathan J. Wilksch,
  • Jason W. H. Tan,
  • Tracy L. Nero,
  • Dianna M. Hocking,
  • Vicki Bennett-Wood,
  • Nancy Wang,
  • Stefanie-Ann Zavras,
  • Carl H. Schiesser,
  • Marija Tauschek,
  • Mark A. Schembri,
  • Trevor Lithgow,
  • Elizabeth L. Hartland,
  • Roy M. Robins-Browne,
  • Michael W. Parker,
  • Ji Yang,
  • Richard A. Strugnell

摘要

Biofilm formation by Klebsiella pneumoniae is mediated by the type 3 fimbriae Mrk, and regulated by MrkH and 3’,5’-cyclic diguanylic acid (c-di-GMP). We sought to identify specific chemical inhibitors of K. pneumoniae biofilm formation that reduced the activity of MrkH. A compound N-(3-cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2-yl)-2-methoxybenzamide, JT71, reduced K. pneumoniae mrkA promoter activity and biofilm formation by 50% without affecting cell viability. Western blot analysis, hemagglutination assays, electron microscopy and qPCR showed that JT71 reduced type 3 fimbriae production, and transcription of mrkA and mrkH. JT71 demonstrated activity against other clinical and multi-drug resistant K. pneumoniae isolates, and a type 3 fimbriate-positive Citrobacter koseri strain. In silico molecule docking was used to illustrate that JT71 could bind directly to the MrkH protein and block its activity. JT71 possesses promising drug-likeness properties and is non-toxic to mammalian cells. Chemical inhibition of transcriptional regulators that control fimbriae expression can inhibit bacterial biofilm formation.