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 | |
| State | Published - Jan 1 2009 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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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 journal › Article
TY - JOUR
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.
PY - 2009/1/1
Y1 - 2009/1/1
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.
UR - http://www.scopus.com/inward/record.url?scp=73149085380&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73149085380&partnerID=8YFLogxK
U2 - 10.1038/nchembio.242
DO - 10.1038/nchembio.242
M3 - Article
C2 - 19915538
AN - SCOPUS:73149085380
VL - 5
SP - 913
EP - 919
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 12
ER -