Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation

Lynette Cegelski, Jerome S. Pinkner, Neal D. Hammer, Corinne K. Cusumano, Chia S. Hung, Erik Chorell, Veronica Åberg, Jennifer N. Walker, Patrick C. Seed, Fredrik Almqvist*, Matthew R. Chapman, Scott J. Hultgren

*Corresponding author for this work

Research output: Contribution to journalArticle

250 Citations (Scopus)

Abstract

Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type 1 pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1-dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1 pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1 pili endows unique anti-biofilm and anti-virulence activities on these compounds.

Original languageEnglish (US)
Pages (from-to)913-919
Number of pages7
JournalNature Chemical Biology
Volume5
Issue number12
DOIs
StatePublished - Jan 1 2009

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Uropathogenic Escherichia coli
Biofilms
Amyloid
Escherichia coli
Urinary Tract Infections
Virulence
Protein Subunits
Enterobacteriaceae
Polymerization
2-hydroxypyridine

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Cegelski, L., Pinkner, J. S., Hammer, N. D., Cusumano, C. K., Hung, C. S., Chorell, E., ... Hultgren, S. J. (2009). Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology, 5(12), 913-919. https://doi.org/10.1038/nchembio.242
Cegelski, Lynette ; Pinkner, Jerome S. ; Hammer, Neal D. ; Cusumano, Corinne K. ; Hung, Chia S. ; Chorell, Erik ; Åberg, Veronica ; Walker, Jennifer N. ; Seed, Patrick C. ; Almqvist, Fredrik ; Chapman, Matthew R. ; Hultgren, Scott J. / Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. In: Nature Chemical Biology. 2009 ; Vol. 5, No. 12. pp. 913-919.
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Cegelski, L, Pinkner, JS, Hammer, ND, Cusumano, CK, Hung, CS, Chorell, E, Åberg, V, Walker, JN, Seed, PC, Almqvist, F, Chapman, MR & Hultgren, SJ 2009, 'Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation', Nature Chemical Biology, vol. 5, no. 12, pp. 913-919. https://doi.org/10.1038/nchembio.242

Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. / Cegelski, Lynette; Pinkner, Jerome S.; Hammer, Neal D.; Cusumano, Corinne K.; Hung, Chia S.; Chorell, Erik; Åberg, Veronica; Walker, Jennifer N.; Seed, Patrick C.; Almqvist, Fredrik; Chapman, Matthew R.; Hultgren, Scott J.

In: Nature Chemical Biology, Vol. 5, No. 12, 01.01.2009, p. 913-919.

Research output: Contribution to journalArticle

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AU - Cegelski, Lynette

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AU - Chorell, Erik

AU - Åberg, Veronica

AU - Walker, Jennifer N.

AU - Seed, Patrick C.

AU - Almqvist, Fredrik

AU - Chapman, Matthew R.

AU - Hultgren, Scott J.

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N2 - Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type 1 pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1-dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1 pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1 pili endows unique anti-biofilm and anti-virulence activities on these compounds.

AB - Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type 1 pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1-dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1 pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1 pili endows unique anti-biofilm and anti-virulence activities on these compounds.

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Cegelski L, Pinkner JS, Hammer ND, Cusumano CK, Hung CS, Chorell E et al. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology. 2009 Jan 1;5(12):913-919. https://doi.org/10.1038/nchembio.242