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Nat Chem Biol. 2009 Dec;5(12):913-9. doi: 10.1038/nchembio.242. Epub 2009 Oct 25.

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

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1
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.

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.

PMID:
19915538
PMCID:
PMC2838449
DOI:
10.1038/nchembio.242
[Indexed for MEDLINE]
Free PMC Article

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