Developments in Mannose‐Based Treatments for Uropathogenic Escherichia coli‐Induced Urinary Tract Infections

Abstract

During their lifetime almost half of women will experience a symptomatic urinary tract infection (UTI) with a further half experiencing a relapse within six months. Currently UTIs are treated with antibiotics, but increasing antibiotic resistance rates highlight the need for new treatments. Uropathogenic Escherichia coli (UPEC) is responsible for the majority of symptomatic UTI cases and thus has become a key pathological target. Adhesion of type one pilus subunit FimH at the surface of UPEC strains to mannose‐saturated oligosaccharides located on the urothelium is critical to pathogenesis. Since the identification of FimH as a therapeutic target in the late 1980s, a substantial body of research has been generated focusing on the development of FimH‐targeting mannose‐based anti‐adhesion therapies. In this review we will discuss the design of different classes of these mannose‐based compounds and their utility and potential as UPEC therapeutics.

Differential recognition of oligomannose isomers by glycan-binding proteins involved in innate and adaptive immunity

“…Mannose has also been tested for its ability to prevent recurrent and incidental urinary tract infection by blocking FimH from adhesion to urinary epithelial cells, but the doses are very high ( 11 , 60 ). The better binding trisaccharide identified in our study could facilitate the design of a glycomimetic reagent with reduced dosage amounts.…”

“…Oligomannoses are functionally important in mediating immune recognition between the host and microorganisms. Expressed on human urinary epithelial cells, oligomannoses are ligands for FimH, an adhesin located on the tip of the type 1 fimbriae of uropathogenic Escherichia coli, enabling the attachment and the subsequent infection of the bacteria (8)(9)(10)(11). Oligomannoses on yeast and microorganisms, on the other hand, are pathogen-associated molecular patterns (PAMPs), which are recognized by a variety of host innate immune receptors including C-type lectin receptors (CLRs), such as DC-SIGN, L-SIGN, Dectin-2, and Langerin (12,13).…”

Targeting a Multidrug-Resistant Pathogen: First Generation Antagonists of Burkholderia cenocepacia’s BC2L-C Lectin

“…AAT combats infection without killing the pathogen: compared to antibiotics, the lack of selective pressure is expected to reduce the appearance of mutations leading to AAT-resistant strains. 7,8 Glycomimetics have proven their worth for AAT as reliable disruptors of carbohydrate/lectin interactions. Designed to emulate the carbohydrate structure and/or function, glycomimetics display improved physicochemical and pharmacokinetic properties (improved oral bioavailability, adjusted polarity, and metabolic stability).…”

A Tale of Two Bioconjugations: pH Controlled Divergent Reactivity of Protein α-oxo-Aldehydes in Competing α-oxo-Mannich and Catalyst-Free Aldol Ligations

“…As 4-methoxyaniline 21 afforded the highest relative conversions to the α-oxo-Mannich product on the peptide, we also synthesized a comparable para-derivatized aniline 24 bearing an α- d -mannose sugar. This sugar has potential therapeutic utility against urinary tract infections as an inhibitor of FimH, the type-one pilus subunit on the surface of uropathogenic E. coli responsible for adhesion to the urothelium . The N -terminal α-oxo aldehyde JVZ007 could also be modified using this mannose derivatized aniline 24 to afford a neoglycoprotein 25 , affording 64% α-oxo-Mannich product and 36% conversion to the aldol product 23 (Figure a and b).…”