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

Nature Chemical Biology volume 5, pages 913–919 (2009)Cite this article

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.

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Figure 1: Curlicide inhibition of in vivo amyloid biogenesis in E. coli.
Figure 2: Curlicide inhibition of in vitro CsgA polymerization.
Figure 3: Curlicide inhibition of curli-dependent UTI89 pellicle formation.
Figure 4: Curlicide inhibition of UTI89 amyloid-dependent and type 1 pili-dependent biofilm formation on PVC.
Figure 5: FN075 attenuation of virulence in vivo.

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Acknowledgements

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.

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Author notes

  1. Lynette Cegelski and Jerome S Pinkner: These authors contributed equally to this work.

Authors and Affiliations

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

    Lynette Cegelski, Jerome S Pinkner, Corinne K Cusumano, Chia S Hung, Jennifer N Walker & Scott J Hultgren

  2. Department of Chemistry, Stanford University, Stanford, California, USA

    Lynette Cegelski

  3. Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA

    Neal D Hammer & Matthew R Chapman

  4. Department of Chemistry, Umeå University, Umeå, Sweden

    Erik Chorell, Veronica Åberg & Fredrik Almqvist

  5. Departments of Pediatrics and Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA

    Patrick C Seed

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Contributions

L.C., J.S.P., N.D.H., C.K.C. and C.S.H. performed and analyzed experiments. E.C. and V.A. synthesized and characterized the molecules. L.C., J.S.P., F.A. and S.J.H. conceptualized and initiated the project. M.R.C., F.A. and S.J.H. oversaw the project and assisted in data analysis. P.C.S. prepared critical reagents. L.C., J.S.P., M.R.C., F.A., C.K.C. and S.J.H. contributed to writing the manuscript. All authors read and edited the manuscript.

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Correspondence to Fredrik Almqvist, Matthew R Chapman or Scott J Hultgren.

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Cegelski, L., Pinkner, J., Hammer, N. et al. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nat Chem Biol 5, 913–919 (2009). https://doi.org/10.1038/nchembio.242

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