Chemical inhibition of MrkH-dependent activation of type 3 fimbriae synthesis and biofilm formation by Klebsiella pneumoniae
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.
Authors
- Michael W. Parker (ORCID: https://orcid.org/0000-0002-3101-1138)
- Trevor J. Lithgow (ORCID: https://orcid.org/0000-0002-0102-7884)
- Richard A. Strugnell (ORCID: https://orcid.org/0000-0003-0614-5641)
- Carl H. Schiesser (ORCID: https://orcid.org/0000-0001-8714-1882)
- Roy M. Robins‐Browne (ORCID: https://orcid.org/0000-0001-9179-7884)
- Jason Tan (ORCID: https://orcid.org/0000-0002-4982-4399)
- Tracy L. Nero (ORCID: https://orcid.org/0000-0002-3393-1843)
- Marija Tauschek
- Jonathan J. Wilksch (ORCID: https://orcid.org/0000-0002-5125-8285)
- Elizabeth L. Hartland (ORCID: https://orcid.org/0000-0003-4254-2863)
- Vicki Bennett‐Wood
- Mark A. Schembri (ORCID: https://orcid.org/0000-0003-4863-9260)
- Dianna M. Hocking (ORCID: https://orcid.org/0000-0002-3485-0586)
- Nancy Wang (ORCID: https://orcid.org/0000-0001-7623-1858)
- Ji Yang (ORCID: https://orcid.org/0009-0001-5320-1098)
- Stefanie-Ann Zavras
Institutions
- Biotechnology Institute (US)
- Royal Children's Hospital (AU)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Australian Regenerative Medicine Institute (AU)
- Hudson Institute of Medical Research (AU)
- Peter Doherty Institute (AU)
- Murdoch Children's Research Institute (AU)
- Monash University (AU)
- St Vincents Institute of Medical Research (AU)
Publication Details
- Journal
- npj Biofilms and Microbiomes
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1038/s41522-025-00834-3
- Citations
- 1
- Primary Topic
- Bacterial biofilms and quorum sensing
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Medical Research Council
- National Health and Medical Research Council