Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel, Germany.
Chembiochem. 2011 May 2;12(7):1066-74. doi: 10.1002/cbic.201000774. Epub 2011 Apr 5.
Bacteria use long proteinaceous appendages, called fimbriae or pili, to adhere to the surfaces of their host cells. Widely distributed among the Enterobacteriacae are type 1 fimbriae that mediate mannose-specific bacterial adhesion through the lectin FimH, located at the fimbrial tips. It is possible to design synthetic mannosides such that they show high affinity for FimH and can thus inhibit mannose-specific bacterial adhesion in a competitive manner. It has been found that mannosidic squaric acid monoamides serve especially well as inhibitors of type 1 fimbriae-mediated bacterial adhesion, but it has remained unclear whether this effect is due to specific inhibition of the bacterial lectin FimH or to unspecific bioconjugation between the lectin's carbohydrate binding site and a squaric acid monoamide. A bioconjugation reaction would result in a covalently crosslinked squaric acid diamide. Here it is shown that covalent inhibition of FimH by mannosidic squaric acid derivatives is very unlikely and that compounds of this type serve rather as excellent specific candidates for low-molecular-weight inhibitors of bacterial adhesion. This has been verified by testing the properties of glycosidic squaric acid monoamides in diamide formation, by two different adhesion assays with a series of selected control compounds, and by molecular docking studies that further support the results obtained in the bioassays.
细菌使用长的蛋白质附属物，称为菌毛或纤毛，来黏附在宿主细胞的表面。肠杆菌科中广泛分布着介导甘露糖特异性细菌黏附的 I 型菌毛，这种黏附是通过位于菌毛尖端的凝集素 FimH 实现的。可以设计合成甘露糖苷，使它们对 FimH 具有高亲和力，从而以竞争性方式抑制甘露糖特异性细菌黏附。已经发现，糖基琥珀酸单酰胺特别适合作为 I 型菌毛介导的细菌黏附抑制剂，但尚不清楚这种作用是由于对细菌凝集素 FimH 的特异性抑制还是由于凝集素的碳水化合物结合位点与琥珀酸单酰胺之间的非特异性生物缀合。生物缀合反应会导致 squaric 酸二酰胺的共价交联。这里表明，糖基琥珀酸衍生物对 FimH 的共价抑制是不太可能的，而这类化合物则是作为细菌黏附低分子量抑制剂的优秀特异性候选物。这通过测试糖苷琥珀酸单酰胺在二酰胺形成中的性质、一系列选定的对照化合物的两种不同黏附测定以及进一步支持生物测定结果的分子对接研究得到了验证。
