Development of Mannopyranoside Therapeutics against Adherent-Invasive Escherichia coli Infections

Abstract

Conspectus 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.

d-Mannose Treatment neither Affects Uropathogenic Escherichia coli Properties nor Induces Stable FimH Modifications

“…UPEC adhesion relies mainly on the interaction between FimH and mannosylated uroplakin proteins on the luminal surfaces of urothelial cells as well as other cellular receptors such as integrins [1,5,8,[13][14][15]. Therefore, FimH antagonists, such as d-mannose, have gained increasing consideration and proven to be effective for the treatment and/or prevention of acute and recurrent UPEC-mediated UTIs [21,22,[24][25][26][27]. Furthermore, d-mannose represents a real alternative to antibiotic regimens, reducing the burden of antibiotic resistance and associated side effects [2,14,31,[34][35][36].…”

“…For this reason, molecules able to interfere with bacterial virulence mechanisms have been proposed to combat UPEC infections [20]. Accordingly, FimH antagonists, such as d-mannose and its derivatives, have emerged as anti-virulence therapeutic strategies for the treatment of UTIs [21][22][23][24][25][26][27]. d-mannose, a C-2 epimer of d-glucose, as well as d-mannose-analogs, prevent FimH-mediated bacterial adhesion through a competitive inhibition mechanism [18,21,22,24,28].…”

FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens

“…Para-substituted biphenyl derivatives were shown to be particularly appealing, owing to their numerous favorable binding interactions within the tyrosine gate. Thus, the structural and functional analyses of a series of O-, C-, and S-linked mannoside derivatives, incorporating the 1,1′-biphenyl pharmacophore and diverse aglycone atoms, demonstrated the suitability of these antagonists, establishing the possibility of further exploring these chemically modified mannosides [ 101 , 102 ]. Furthermore, it was shown that the biphenyl group linked to mannosides can be efficiently absorbed if orally administered [ 54 , 88 ].…”

Comparative Study of Aryl O-, C-, and S-Mannopyranosides as Potential Adhesion Inhibitors toward Uropathogenic E. coli FimH

“…The FimH bacterial lectins adhere to the highly mannosylated glycoprotein uroplakin 1a [9,10] on the bladder cells and on glycoprotein 2 (GP2) exclusively expressed in the small intestine [7,11]. Once the infection process is initiated, it is usually followed by thick biofilm formation [12,13].…”

“…Given that bacterial adhesion to host cells is the preliminary step toward the release of toxic proteins, the design of potent E. coli FimH antagonists has been the target of several efforts [15,16]. Several glycomimetic analogs of the naturally occurring complex oligomannosides have been synthesized [8,10] that provided potent α-D-mannopyranoside-based antiadhesins. Since small molecule antagonists represent the foremost choice of the pharmaceutical industry, these glycomimetics constitute most promising candidates for the replacement of the natural lead oligomannosides onto which E. coli adhere to [10,17].…”