Preventing bacterial adhesion to host cells is a provocative and alternative approach to traditional antibiotic treatments given the increasing microbial resistance. A brief overview of common antibiotic treatments is described in light of their respective resistance and remaining susceptibility. This strategy has been seriously considered in the context of adherent-invasive infections in Crohn’s disease and urinary tract infections in particular. The adhesions of various pathogenic Escherichia coli strains to host cells are primarily mediated through carbohydrate–protein interactions involving bacterial organelles called fimbriae that can recognize specific glycoconjugate receptors on host cells. Of particular interest are the FimH and PapG fimbriae, which bind to mannosylated glycoproteins and glycolipids of the galabiose series, respectively. Therefore, blocking FimH- and PapG-mediated bacterial adhesion to uroepithelial cells by high-affinity carbohydrate antagonists constitutes a challenging therapeutic target of high interest. This is of particular interest since bacterial adhesion to host cells is a parameter unlikely to be the subject of bacterial mutations without affecting the carbohydrate ligand binding interactions at the basis of the recognition and infection processes. To date, there have been several families of potent FimH antagonists that include natural O-linked as well as unnatural analogues of α-d-mannopyranosides. These observations led to a thorough understanding of the intimate binding site interactions that helped to reveal the so-called “tyrosine gate mechanism” at the origin of the strong necessary interactions with sugar-possessing hydrophobic aglycones. By modification of the aglycones of single monosaccharidic d-mannopyranosides, it was possible to replace the natural complex oligomannoside structure by simpler ones. An appealing and successful series of analogues have been disclosed, including nanomolecular architectures such as dendrimers, polymers, and liposomes. In addition, the data were compared to the above multivalent architectures and confirmed the possibility of working with small sugar candidates. This Account primarily concentrates on the most promising types of FimH inhibitors belonging to the family of α-C-linked mannopyranosides. However, one of the drawbacks associated with C-mannopyranosides has been that they were believed to be in the inverted chair conformation, which is obviously not recognized by the E. coli FimH. To decipher this situation, various synthetic approaches, conformational aspects, and restrictions are discussed using molecular modeling, high-field NMR spectroscopy, and X-ray analysis. These combined techniques pointed to the fact that several α-C-linked mannopyranosides do exist in the required ⁴C₁ chair conformation. Ultimately, recent findings in this growing field of interest culminated in the identification of drug candidates that have reached clinical phase I.

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甘露吡喃糖苷对粘附侵袭性大肠杆菌感染的治疗方法的发展

考虑到微生物耐药性的增加，防止细菌粘附于宿主细胞是传统抗生素治疗的一种替代方法。根据它们各自的耐药性和剩余药敏性，对常用抗生素治疗进行了简要概述。在克罗恩病的黏附性感染尤其是尿路感染的情况下，已经认真考虑了该策略。各种致病性大肠杆菌的黏附对宿主细胞的毒株主要是通过碳水化合物-蛋白质相互作用来介导的，这种相互作用涉及细菌菌毛，称为菌毛，可以识别宿主细胞上特定的糖缀合物受体。特别感兴趣的是FimH和PapG菌毛，它们分别结合甘露糖系列的甘露糖基化糖蛋白和糖脂。因此，通过高亲和力的碳水化合物拮抗剂阻断FimH和PapG介导的细菌对尿道上皮细胞的粘附构成了具有高度挑战性的治疗目标。这是特别令人感兴趣的，因为细菌与宿主细胞的粘附是一个参数，在识别和感染过程的基础上，该参数不太可能成为细菌突变的对象，而不会影响碳水化合物与配体的结合相互作用。迄今为止，d-甘露吡喃糖苷。这些观察结果导致对紧密结合位点相互作用的透彻理解，有助于揭示所谓的“酪氨酸门机制”，其与具有糖基的疏水性糖苷配基之间的强而有必要的相互作用产生了。通过单monosaccharidic的糖苷配基的修饰d-甘露吡喃糖苷，可以用更简单的取代天然复杂的低聚甘露糖苷结构。已经公开了一种吸引人且成功的类似物系列，包括纳米分子结构，例如树状聚合物，聚合物和脂质体。此外，将数据与上述多价结构进行了比较，并证实了使用小糖候选物的可能性。该帐户主要集中在属于α-C连接的甘露吡喃糖苷家族中最有前途的FimH抑制剂类型。然而，与C-甘露糖吡喃糖苷相关的缺点之一是，据信它们以倒椅构象存在，这显然未被大肠杆菌识别。FimH。为了解释这种情况，使用分子建模，高场NMR光谱和X射线分析讨论了各种合成方法，构象方面和限制条件。这些组合技术指出了这样一个事实，即在所需的⁴ C ₁椅子构象中确实存在几种α-C连接的甘露吡喃糖苷。最终，在这个不断增长的兴趣领域中的最新发现最终达到了鉴定已进入临床I期的候选药物的高潮。