posted on 2017-05-04, 00:00authored byKatharina Mayer, Deniz Eris, Oliver Schwardt, Christoph P. Sager, Said Rabbani, Simon Kleeb, Beat Ernst
Frequent antibiotic treatment of
urinary tract infections has resulted in the emergence of antimicrobial
resistance, necessitating alternative treatment options. One such
approach centers around FimH antagonists that block the bacterial
adhesin FimH, which would otherwise mediate binding of uropathogenic Escherichia coli to the host urothelium to trigger the infection.
Although the FimH lectin can adopt three distinct conformations, the
evaluation of FimH antagonists has mainly been performed with a truncated
construct of FimH locked in one particular conformation. For a successful
therapeutic application, however, FimH antagonists should be efficacious
against all physiologically relevant conformations. Therefore, FimH
constructs with the capacity to adopt various conformations were applied.
By examining the binding properties of a series of FimH antagonists
in terms of binding affinity and thermodynamics, we demonstrate that
depending on the FimH construct, affinities may be overestimated by
a constant factor of 2 orders of magnitude. In addition, we report
several antagonists with excellent affinities for all FimH conformations.