Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation.
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.
Cegelski
Lynette
L
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Pinkner
Jerome S
JS
Hammer
Neal D
ND
Cusumano
Corinne K
CK
Hung
Chia S
CS
Chorell
Erik
E
Aberg
Veronica
V
Walker
Jennifer N
JN
Seed
Patrick C
PC
Almqvist
Fredrik
F
Chapman
Matthew R
MR
Hultgren
Scott J
SJ
D000682:Amyloid / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018441:Biofilms / Q000254:growth & development*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D048168:Escherichia coli K12 / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence
D000682:Amyloid; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D054852:Small Molecule Libraries; C489688:csgA protein, E coli; C077481:Crl protein, Bacteria