Institute of Molecular Pharmacy, Department of Pharmaceutical Sciences, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
J Med Chem. 2017 Jul 13;60(13):5646-5662. doi: 10.1021/acs.jmedchem.7b00342. Epub 2017 May 11.
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.
频繁使用抗生素治疗尿路感染导致了抗菌药物耐药性的出现，因此需要替代的治疗方案。一种方法是针对 FimH 拮抗剂，该拮抗剂可阻断细菌黏附素 FimH，否则 FimH 会介导尿路致病性大肠杆菌与宿主尿路上皮的结合，从而引发感染。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针对锁定在一种特定构象的 FimH 的截断构建体进行的。然而，为了成功的治疗应用，FimH 拮抗剂应该对所有生理相关的构象都有效。因此，应用了能够采用各种构象的 FimH 构建体。通过考察一系列 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，根据 FimH 构建体的不同，亲和力可能会被高估 2 个数量级。此外，我们还报告了几种对所有 FimH 构象均具有优异亲和力的拮抗剂。
