Biomimickry of UPEC Cytoinvasion: A Novel Concept for Improved Drug Delivery in UTI.

Clara Pichl,Lukas Neutsch,Bernhard Dunkl,Franz Gabor,Michael Wirth,Bernhard Brauner

doi:10.3390/pathogens5010016

Abstract

Urinary tract infections (UTIs) are among the most common bacterial infections. In an increasing number of cases, pathogen (multi-)resistance hampers durable treatment success via the standard therapies. On the functional level, the activity of urinary excreted antibiotics is compromized by the efficient tissue colonization mechanism of uropathogenic Escherichia coli (UPEC). Advanced drug delivery systems aim at exploiting a glycan-mediated targeting mechanism, similar to the UPEC invasion pathway, to increase bioavailability. This may be realized by conjugation of intravesically applied drugs or drug carriers to chosen plant lectins. Higher local drug concentrations in or nearby bacterial reservoirs may be gained, with higher chances for complete eradication. In this study, preliminary parameters to clarify the potential of this biorecognitive approach were evaluated. Glycan-triggered interaction cascades and uptake processes of several plant lectins with distinct carbohydrate specificities were characterized, and wheat germ agglutinin (WGA) could be identified as the most promising targeter for crossing the urothelial membrane barrier. In partially differentiated primary cells, intracellular accumulation sites were largely identical for GlcNAc- and Mannose-specific lectins. This indicates that WGA-mediated delivery may also enter host cells via the FimH-dependent uptake pathway.

Highlights

Urinary tract infections (UTIs) rank among the most common bacterial infections and represent a severe burden to the society, with significant impact on patient quality of life and overall health care costs [1]
The uptake behaviour of fluorescein-labelled wheat germ agglutinin (WGA) and LCA were compared in detail, since WGA harbours the highest binding potential and LCA targets glycan epitopes similar to those recognized by FimH [6]
Quenching ratios around 40% for fluorescein-labelled WGA (fWGA) and 71% for fLCA pointed to an efficient uptake into late endosomal/lysosomal compartments

Summary

Introduction

Urinary tract infections (UTIs) rank among the most common bacterial infections and represent a severe burden to the society, with significant impact on patient quality of life and overall health care costs [1]. In UTI, a key step in host colonization by uropathogenic Escherichia coli (UPEC) is the mannose-mediated adhesion of the bacterial FimH lectin domains to membrane proteins and lipids. This FimH/carbohydrate interaction can trigger active uptake processes, allowing the bacteria to cross the rigid membrane barrier and proliferate in cytosolic or membrane-bound compartments, where they are protected from antibiotics and the host immune system. Release from these reservoirs back into the bladder lumen after a certain lag time is considered a main cause for recurrent infections [2,3]

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