Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Jerome S. Pinkner, Han Remaut, Floris Buelens, Eric Miller, Veronica Åberg, Nils Pemberton, Mattias Hedenström, Andreas Larsson, Patrick Seed, Gabriel Waksman*, Scott J. Hultgren, Fredrik Almqvist

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

253 Scopus citations


A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by ≈90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.

Original languageEnglish (US)
Pages (from-to)17897-17902
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number47
StatePublished - Nov 21 2006


  • Antimicrobials
  • Chaperone-usher pathway
  • Pilicide
  • Urinary tract infection

ASJC Scopus subject areas

  • General


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