Journal article
Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI
ChemMedChem, Vol.11(4), pp.367-373
02/17/2016
DOI: 10.1002/cmdc.201600006
PMCID: PMC4818977
PMID: 26812660
Abstract
Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ray structure of lead mannosides and then designed mannosides with improved drug-like properties. We show that cyclizing the carboxamide onto the biphenyl B-ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2-methyl-4-(1-oxo-1,2-dihydroisoquinolin-7-yl)phenyl α-d-mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N-Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22, as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria-mediated hemagglutination and prevent biofilm formation by UPEC with single-digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.
Details
- Title: Subtitle
- Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI
- Creators
- Cassie Jarvis - Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., St. Louis, MO, 63110, USAZhenfu Han - Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., St. Louis, MO, 63110, USAVasilios Kalas - Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USARoger Klein - Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USAJerome S Pinkner - Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USABradley Ford - Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USAJana Binkley - Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USACorinne K Cusumano - Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USAZachary Cusumano - Fimbrion Therapeutics Inc., 4041 Forest Park Ave., St. Louis, MO, 63108, USALaurel Mydock-McGrane - Fimbrion Therapeutics Inc., 4041 Forest Park Ave., St. Louis, MO, 63108, USAScott J Hultgren - Washington University School of Medicine, Center for Women's Infectious Disease Research (cWIDR), 660 S. Euclid Ave., St. Louis, MO, 63110, USA. hultgren@wusm.wustl.eduJames W Janetka - Washington University School of Medicine, Center for Women's Infectious Disease Research (cWIDR), 660 S. Euclid Ave., St. Louis, MO, 63110, USA. janetka@biochem.wustl.edu
- Resource Type
- Journal article
- Publication Details
- ChemMedChem, Vol.11(4), pp.367-373
- DOI
- 10.1002/cmdc.201600006
- PMID
- 26812660
- PMCID
- PMC4818977
- NLM abbreviation
- ChemMedChem
- ISSN
- 1860-7179
- eISSN
- 1860-7187
- Publisher
- Germany
- Grant note
- R43 AI106112 / NIAID NIH HHS R01 DK051406 / NIDDK NIH HHS 1R43AI106112-01A1 / NIAID NIH HHS 1RC1K086378 / CCR NIH HHS
- Language
- English
- Date published
- 02/17/2016
- Academic Unit
- Pathology
- Record Identifier
- 9984047699502771
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