Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic E. coli

PLoS Pathogens

John P. Sumida¹  Shivani Gupta²  Wendy E. Thomas²  Gianluca Interlandi²  Victoria B. Rodriguez²  Veronika Tchesnokova³  Evgeni V. Sokurenko³  Dagmara I. Kisiela³  Hovhannes Avagyan³  Aachal Jalan³  Yan Liu⁴  Xue-Ru Wu⁴  Roland K. Strong⁵  Della Friend⁵ 

[1] Analytical Biopharmacy Core, University of Washington, Seattle, Washington, United States of America;Department of Bioengineering, University of Washington, Seattle, Washington, United States of America;Department of Microbiology, University of Washington, Seattle, Washington, United States of America;Department of Urology, New York University School of Medicine, New York, New York, United States of America;Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

关键词: Mannose;    Antibodies;    Bacterial biofilms;    Enzyme-linked immunoassays;    Adhesins;    Lectins;    Crystal structure;    Pili;    fimbriae;   

DOI  :  10.1371/journal.ppat.1004857

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY