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

doi:10.1038/nchembio.242

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

370 Scopus citations

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 language	English (US)
Pages (from-to)	913-919
Number of pages	7
Journal	Nature Chemical Biology
Volume	5
Issue number	12
DOIs	https://doi.org/10.1038/nchembio.242
State	Published - Dec 2009

Funding

We gratefully acknowledge the expertise of W. Beatty (Imaging Facility, Washington University School of Medicine) and of A. Olofsson (Umeå Centre for Molecular Pathogenesis, Umeå University). This study was supported in part by the Swedish Natural Science Research Council and the Knut and Alice Wallenberg Foundation. The authors acknowledge funding from the US National Institutes of Health to S.J.H. (AI02549, AI048689, AI049950 and P50 DK64540), M.R.C. (AI073847), P.C.S. (K12HD00850 and K08DK074443) and L.C. (T32A107172). L.C. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1038/nchembio.242

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@article{18a9458519424892aaa726051bd0f703,

title = "Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation",

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.",

author = "Lynette Cegelski and Pinkner, {Jerome S.} and Hammer, {Neal D.} and Cusumano, {Corinne K.} and Hung, {Chia S.} and Erik Chorell and Veronica {\AA}berg and Walker, {Jennifer N.} and Seed, {Patrick C.} and Fredrik Almqvist and Chapman, {Matthew R.} and Hultgren, {Scott J.}",

note = "Funding Information: We gratefully acknowledge the expertise of W. Beatty (Imaging Facility, Washington University School of Medicine) and of A. Olofsson (Ume{\aa} Centre for Molecular Pathogenesis, Ume{\aa} University). This study was supported in part by the Swedish Natural Science Research Council and the Knut and Alice Wallenberg Foundation. The authors acknowledge funding from the US National Institutes of Health to S.J.H. (AI02549, AI048689, AI049950 and P50 DK64540), M.R.C. (AI073847), P.C.S. (K12HD00850 and K08DK074443) and L.C. (T32A107172). L.C. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund.",

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doi = "10.1038/nchembio.242",

language = "English (US)",

volume = "5",

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journal = "Nature Chemical Biology",

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T1 - Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation

AU - Cegelski, Lynette

AU - Pinkner, Jerome S.

AU - Hammer, Neal D.

AU - Cusumano, Corinne K.

AU - Hung, Chia S.

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.

N1 - Funding Information: We gratefully acknowledge the expertise of W. Beatty (Imaging Facility, Washington University School of Medicine) and of A. Olofsson (Umeå Centre for Molecular Pathogenesis, Umeå University). This study was supported in part by the Swedish Natural Science Research Council and the Knut and Alice Wallenberg Foundation. The authors acknowledge funding from the US National Institutes of Health to S.J.H. (AI02549, AI048689, AI049950 and P50 DK64540), M.R.C. (AI073847), P.C.S. (K12HD00850 and K08DK074443) and L.C. (T32A107172). L.C. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund.

PY - 2009/12

Y1 - 2009/12

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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ER -

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

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