Journal
NATURE CHEMICAL BIOLOGY
Volume 5, Issue 12, Pages 913-919Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.242
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Funding
- Swedish Natural Science Research Council
- Knut and Alice Wallenberg Foundation
- US National Institutes of Health [AI02549, AI048689, AI049950, P50 DK64540, AI073847, K12HD00850, K08DK074443, T32A107172]
- Burroughs Wellcome Fund
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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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