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

NPJ Biofilms Microbiomes. 2025 Nov 20;11(1):212. doi: 10.1038/s41522-025-00834-3.

Jonathan J Wilksch ^# ¹ ², Jason W H Tan ^# ¹, Tracy L Nero ^# ³, Dianna M Hocking ¹ ⁴, Vicki Bennett-Wood ¹, Nancy Wang ¹ ⁴, Stefanie-Ann Zavras ⁵, Carl H Schiesser ⁵, Marija Tauschek ¹, Mark A Schembri ⁶, Trevor Lithgow ², Elizabeth L Hartland ¹ ⁷, Roy M Robins-Browne ¹, Michael W Parker ³ ⁸, Ji Yang ¹, Richard A Strugnell ⁹ ¹⁰

Affiliations

1 Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.
2 Infection & Immunity Program, Biomedicine Discovery Institute & Department of Microbiology, Monash University, Clayton, VIC, Australia.
3 Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
4 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.
5 ARC Centre of Excellence for Free Radical Chemistry and Biotechnology and the School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
6 Institute for Molecular Bioscience (IMB), and School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.
7 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Australia and Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
8 Structural Biology Laboratory, St Vincent's Institute of Medical Research, Melbourne, VIC, Australia.
9 Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia. [email protected].
10 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia. [email protected].
# Contributed equally.

PMID: 41266360 DOI: 10.1038/s41522-025-00834-3

Abstract

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-180539

JT71

99.30%, MrkH Inhibitor

Bacterial

Infection

Name
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