title: Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI.
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.
authors.affiliation: Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Cassie
authors.initials: C
authors.lastname: Jarvis
authors.affiliation: Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Zhenfu
authors.initials: Z
authors.lastname: Han
authors.affiliation: Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Kalas
authors.affiliation: Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Klein
authors.affiliation: Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.affiliation: Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Ford
authors.affiliation: Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Binkley
authors.affiliation: Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: Corinne K
authors.initials: CK
authors.lastname: Cusumano
authors.affiliation: Fimbrion Therapeutics Inc., 4041 Forest Park Ave., St. Louis, MO, 63108, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Cusumano
authors.affiliation: Fimbrion Therapeutics Inc., 4041 Forest Park Ave., St. Louis, MO, 63108, USA.
authors.forename: Laurel
authors.initials: L
authors.lastname: Mydock-McGrane
authors.affiliation: Washington University School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave., St. Louis, MO, 63110, USA. hultgren@wusm.wustl.edu.|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.edu.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.affiliation: Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 S. Euclid Ave., St. Louis, MO, 63110, USA. janetka@biochem.wustl.edu.|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.
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
mesh_terms: D018830:Adhesins, Escherichia coli / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002908:Chronic Disease; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D036781:Fimbriae Proteins / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D001743:Urinary Bladder / Q000382:microbiology; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; D007546:Isoquinolines; D008362:Mannosides; C058769:fimH protein, E coli; D036781:Fimbriae Proteins
keywords: FimH; biofilms; mannosides; urinary tract infections; uropathogenic E. coli
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