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.

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尿路感染：细菌凝集素FimH的哪些构型在治疗上相关？

尿道感染的频繁抗生素治疗导致出现了抗药性，因此需要其他治疗选择。一种这样的方法围绕着FimH拮抗剂，该拮抗剂阻断细菌粘附素FimH，否则会介导尿毒原性大肠杆菌的结合到宿主尿路上皮触发感染。尽管FimH凝集素可以采用三种不同的构象，但FimH拮抗剂的评估主要是通过将FimH的截短构建体锁定在一个特定构象中来进行的。但是，对于成功的治疗应用，FimH拮抗剂应对所有生理相关构象有效。因此，使用了具有采取各种构象能力的FimH构建体。通过检查一系列FimH拮抗剂在结合亲和力和热力学方面的结合特性，我们证明了根据FimH构建体，亲和力可能被2个数量级的常数因子高估。此外，我们报告了几种对所有FimH构象都具有出色亲和力的拮抗剂。