Aberg Veronica, Hedenström Mattias, Pinkner Jerome S, Hultgren S J, Almqvist Fredrik
Organic Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Org Biomol Chem. 2005 Nov 7;3(21):3886-92. doi: 10.1039/b509376g. Epub 2005 Sep 5.
Virulence-associated organelles, termed pili or fimbriae, are assembled via the highly conserved chaperone-usher pathway in a vast number of pathogenic bacteria. Substituted bicyclic 2-pyridones, pilicides, inhibit pilus formation, possibly by interfering with the active site residues Arg8 and Lys112 of chaperones in uropathogenic E. coli. In this article we describe the synthesis and evaluation of nine analogues of a biologically active pilicide. Derivatization was performed with respect to its C-terminal features and the affinities for the chaperone PapD were studied with 1H relaxation-edited NMR spectroscopy. It could be concluded that the carboxylic acid functionality and also its spatial location was important for binding. In all cases, binding was significantly reduced or even abolished when the carboxylic acid was replaced by other substituents. In addition, in vivo results from a hemagglutination assay are presented where the derivatives have been evaluated for their ability to inhibit pilus formation in uropathogenic E. coli.
毒力相关细胞器，称为菌毛或纤毛，通过高度保守的伴侣-usher途径在大量致病细菌中组装。取代的双环2-吡啶酮，即菌毛抑制剂，可能通过干扰尿路致病性大肠杆菌中伴侣蛋白的活性位点残基Arg8和Lys112来抑制菌毛形成。在本文中，我们描述了一种具有生物活性的菌毛抑制剂的九种类似物的合成和评估。针对其C端特征进行衍生化，并通过1H弛豫编辑核磁共振光谱研究了对伴侣蛋白PapD的亲和力。可以得出结论，羧酸官能团及其空间位置对于结合很重要。在所有情况下，当羧酸被其他取代基取代时，结合显著降低甚至消除。此外，还给出了血凝试验的体内结果，其中评估了衍生物抑制尿路致病性大肠杆菌中菌毛形成的能力。
