title: Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic E. coli.
abstract: Attachment proteins from the surface of eukaryotic cells, bacteria and viruses are critical receptors in cell adhesion or signaling and are primary targets for the development of vaccines and therapeutic antibodies. It is proposed that the ligand-binding pocket in receptor proteins can shift between inactive and active conformations with weak and strong ligand-binding capability, respectively. Here, using monoclonal antibodies against a vaccine target protein - fimbrial adhesin FimH of uropathogenic Escherichia coli, we demonstrate that unusually strong receptor inhibition can be achieved by antibody that binds within the binding pocket and displaces the ligand in a non-competitive way. The non-competitive antibody binds to a loop that interacts with the ligand in the active conformation of the pocket but is shifted away from ligand in the inactive conformation. We refer to this as a parasteric inhibition, where the inhibitor binds adjacent to the ligand in the binding pocket. We showed that the receptor-blocking mechanism of parasteric antibody differs from that of orthosteric inhibition, where the inhibitor replaces the ligand or allosteric inhibition where the inhibitor binds at a site distant from the ligand, and is very potent in blocking bacterial adhesion, dissolving surface-adherent biofilms and protecting mice from urinary bladder infection.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Dagmara I
authors.initials: DI
authors.lastname: Kisiela
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Hovhannes
authors.initials: H
authors.lastname: Avagyan
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Della
authors.initials: D
authors.lastname: Friend
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Aachal
authors.initials: A
authors.lastname: Jalan
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors.forename: Shivani
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Interlandi
authors.affiliation: Department of Urology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Veronika
authors.initials: V
authors.lastname: Tchesnokova
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Rodriguez
authors.affiliation: Analytical Biopharmacy Core, University of Washington, Seattle, Washington, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Sumida
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
authors.affiliation: Department of Urology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Thomas
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Evgeni V
authors.initials: EV
authors.lastname: Sokurenko
mesh_terms: D018830:Adhesins, Escherichia coli / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001422:Bacterial Adhesion; D005260:Female; D036781:Fimbriae Proteins / Q000378:metabolism*; D010861:Fimbriae, Bacterial / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D056689:Uropathogenic Escherichia coli / Q000378:metabolism*
chemical_list: D018830:Adhesins, Escherichia coli; D000911:Antibodies, Monoclonal; C058769:fimH protein, E coli; D036781:Fimbriae Proteins