4CST

Crystal structure of FimH in complex with 3'-Chloro-4'-(alpha-D-mannopyranosyloxy)-biphenyl-4-carbonitrile

Summary for 4CST

• Entry DOI: 10.2210/pdb4cst/pdb
• Related: 4CSS 4CSY
• Descriptor: PROTEIN FIMH, 3'-chloro-4'-(alpha-D-mannopyranosyloxy)biphenyl-4-carbonitrile (3 entities in total)
• Functional Keywords: sugar binding protein, fimh antagonists, type i pili, uti, upec, adhesin
• Biological source: ESCHERICHIA COLI K-12
• Total number of polymer chains: 1
• Total formula weight: 17832.28

Authors

Kleeb, S.,Pang, L.,Mayer, K.,Sigl, A.,Eris, D.,Preston, R.C.,Zihlmann, P.,Abgottspon, D.,Hutter, A.,Scharenberg, M.,Jian, X.,Navarra, G.,Rabbani, S.,Smiesko, M.,Luedin, N.,Jakob, R.P.,Schwardt, O.,Maier, T.,Sharpe, T.,Ernst, B. (deposition date: 2014-03-10, release date: 2015-02-25, Last modification date: 2024-11-13)

Primary citation

Ernst, B.,Kleeb, S.,Pang, L.,Mayer, K.,Eris, D.,Sigl, A.,Zihlmann, P.,Preston, R.C.,Sharpe, T.,Jakob, R.,Abgottspon, D.,Hutter, A.S.,Scharenberg, M.,Jiang, X.,Navarra, G.,Rabbani, S.,Smiesko, M.,Ludin, N.,Bezencon, J.,Schwardt, O.,Maier, T.
Fimh Antagonists: Bioisosteres to Improve the in Vitro and in Vivo Pk/Pd Profile.
J.Med.Chem., 58:2221-, 2015

PubMed Abstract: Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl α-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(α-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.

PubMed: 25666045
DOI: 10.1021/JM501524Q

Experimental method

X-RAY DIFFRACTION (1.1 Å)