Cegelski Lynette, Pinkner Jerome S, Hammer Neal D, Cusumano Corinne K, Hung Chia S, Chorell Erik, Aberg Veronica, Walker Jennifer N, Seed Patrick C, Almqvist Fredrik, Chapman Matthew R, Hultgren Scott J
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Nat Chem Biol. 2009 Dec;5(12):913-9. doi: 10.1038/nchembio.242. Epub 2009 Oct 25.
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.
卷曲菌素是由尿路致病性大肠杆菌（UPEC）和其他肠杆菌科细菌产生的功能性细胞外淀粉样纤维。稠环2-吡啶酮，如FN075和BibC6，可抑制UPEC中卷曲菌素的生物合成，并阻止主要卷曲菌素亚基蛋白CsgA的体外聚合。卷曲菌素抑制剂FN075和BibC6与其他称为菌毛抑制剂的稠环2-吡啶酮具有共同的化学谱系。菌毛抑制剂可抑制1型菌毛的组装，而1型菌毛是尿路感染发病机制所必需的。值得注意的是，卷曲菌素抑制剂保留了菌毛抑制剂的活性，并抑制了卷曲菌素依赖性和1型依赖性生物膜。此外，用FN075对UPEC进行预处理可显著降低小鼠尿路感染模型中的毒力。卷曲菌素和1型菌毛在促进UPEC生物膜形成方面发挥了独特且独立的作用，并且卷曲菌素在体内提供了适应性优势。因此，FN075阻断卷曲菌素和1型菌毛生物合成的能力赋予了这些化合物独特的抗生物膜和抗毒力活性。
