Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
Department Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland.
ChemMedChem. 2019 Apr 3;14(7):749-757. doi: 10.1002/cmdc.201900051. Epub 2019 Feb 22.
Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d-mannosides leads to compounds with perfect π-π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as H, N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.
抗菌药物耐药性已成为治疗尿路感染的严重问题。在这种情况下，针对 FimH 的抗黏附方法引起了相当大的关注，FimH 是一种细菌凝集素，可使大肠杆菌附着在宿主细胞上。FimH 在没有切变力的情况下可以采用低/中亲和力状态，而在存在切变力的情况下可以采用高亲和力状态。直到最近，尽管治疗性拮抗剂主要应该与低亲和力状态结合，但主要还是研究了高亲和力状态。在本通讯中，我们证明了联苯 α-d-甘露糖苷的氟化导致与 FimH 的酪氨酸门具有完美的π-π堆积相互作用的化合物，分别对低亲和力状态和高亲和力状态具有低纳摩尔至亚纳摩尔的 K 值。FimH 配体的全氟化联苯基团和 Tyr48 的面对面排列通过晶体结构以及 H、N-HSQC NMR 分析得到了证实。最后，氟化改善了预测口服可用性的药代动力学参数。
