University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia.
Molecular Pharmacy Group, Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
Eur J Med Chem. 2021 Feb 5;211:113093. doi: 10.1016/j.ejmech.2020.113093. Epub 2020 Dec 9.
Bacterial resistance has become an important challenge in the treatment of urinary tract infections. The underlying resistance mechanisms can most likely be circumvented with an antiadhesive approach, antagonizing the lectin FimH located at the tip of fimbriae of uropathogenic E. coli. Here we report on a novel series of FimH antagonists based on the 1-(α-d-mannopyranosyl)-4-phenyl-1,2,3-triazole scaffold, designed to incorporate carboxylic acid or ester functions to interact with FimH Arg98. The most potent representative of the series, ester 11e, displayed a K value of 7.6 nM for the lectin domain of FimH with a general conclusion that all esters outperform carboxylates in terms of affinity. Surprisingly, all compounds from this new series exhibited improved binding affinities also for the R98A mutant, indicating another possible interaction contributing to binding. Our study on 1-(α-d-mannopyranosyl)-4-phenyl-1,2,3-triazole-based FimH antagonists offers proof that targeting Arg98 side chain by a "chemical common sense", i.e. by introduction of the acidic moiety to form ionic bond with Arg98 is most likely unsuitable approach to boost FimH antagonists' potency.
细菌耐药性已成为治疗尿路感染的重要挑战。通过抗黏附的方法，拮抗位于尿路致病性大肠杆菌菌毛顶端的凝集素 FimH，很可能规避潜在的耐药机制。在此，我们报道了一系列基于 1-(α-d-甘露吡喃糖基)-4-苯基-1,2,3-三唑支架的新型 FimH 拮抗剂，旨在引入羧酸或酯官能团与 FimH Arg98 相互作用。该系列中最有效的代表物 11e 酯对 FimH 的凝集素结构域的 K 值为 7.6 nM，总体结论是所有酯在亲和力方面均优于羧酸。令人惊讶的是，该新系列的所有化合物对 R98A 突变体的结合亲和力也有所提高，表明另一种可能的相互作用有助于结合。我们对基于 1-(α-d-甘露吡喃糖基)-4-苯基-1,2,3-三唑的 FimH 拮抗剂的研究证明，通过“常识化学”靶向 Arg98 侧链，即引入酸性部分与 Arg98 形成离子键，很可能不是提高 FimH 拮抗剂效力的合适方法。
