Journal article
Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists
Journal of medicinal chemistry, Vol.53(12), pp.4779-4792
06/24/2010
DOI: 10.1021/jm100438s
PMCID: PMC2894565
PMID: 20507142
Abstract
FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic
E. coli
(UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on α-D-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biaryl mannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and sub micromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including π-π interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt-bridge. Dimeric analogs linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections.
Details
- Title: Subtitle
- Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists
- Creators
- Zhenfu Han - Department of Biochemistry and Molecular Biophysics, Washington University School of MedicineJerome S Pinkner - Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of MedicineBradley Ford - Department of Pathology and Immunology, Washington University School of MedicineRobert Obermann - Department of Biochemistry and Molecular Biophysics, Washington University School of MedicineWilliam Nolan - Department of Biochemistry and Molecular Biophysics, Washington University School of MedicineScott A Wildman - Department of Biochemistry and Molecular Biophysics, Washington University School of MedicineDoug Hobbs - Department of Biochemistry and Molecular Biophysics, Washington University School of MedicineTom Ellenberger - Department of Biochemistry and Molecular Biophysics, Washington University School of MedicineCorinne K Cusumano - Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of MedicineScott J Hultgren - Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of MedicineJames W Janetka - Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.53(12), pp.4779-4792
- DOI
- 10.1021/jm100438s
- PMID
- 20507142
- PMCID
- PMC2894565
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Language
- English
- Date published
- 06/24/2010
- Academic Unit
- Pathology
- Record Identifier
- 9984047617502771
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