title: Mannose-derived FimH antagonists: a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn's disease.
abstract: BACKGROUND
  Type 1 pili are utilized by Gram-negative bacteria to adhere to host tissue and thus are a key virulence factor in urinary tract infections (UTIs) and Crohn's disease (CD). This adhesion is mediated through specific binding of the terminal adhesin, FimH, to mannosylated host glycoproteins. FimH is essential for UTI pathogenesis and thus is a promising therapeutic target.
  
  
  METHODS
  Herein, we review the structural frameworks of FimH antagonists disclosed in the patent literature. X-ray crystallographic binding studies of D-mannose and early FimH antagonists have uncovered key molecular interactions. Exploiting this knowledge, mannosides with extraordinarily high binding affinities have been designed. Structure-activity relationships (SAR) and structure-property relationship (SPR) studies have resulted in the rapid development of orally bioavailable FimH antagonists with promising therapeutic potential for UTI and CD.
  
  
  CONCLUSIONS
  It is our opinion that biaryl or 'two-ring' mannosides, which represent the largest and most thoroughly tested class of FimH antagonists, also hold the most promise as a novel treatment for UTIs. These antagonists have also been shown to have efficacy in treating CD. Judging from the strong preclinical data, we predict that one or more FimH antagonists will be entering the clinic within the next 1-2 years.
authors.affiliation: a Fimbrion Therapeutics, Inc ., Saint Louis , MO , USA.
authors.forename: Laurel K
authors.initials: LK
authors.lastname: Mydock-McGrane
authors.affiliation: a Fimbrion Therapeutics, Inc ., Saint Louis , MO , USA.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Cusumano
authors.affiliation: b Department of Biochemistry and Molecular Biophysics , Center for Women's Infectious Disease Research (cWIDR), Washington University School of Medicine , Saint Louis , MO , USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
mesh_terms: D018830:Adhesins, Escherichia coli; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D003424:Crohn Disease / Q000188:drug therapy* / Q000382:microbiology; D015195:Drug Design; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008358:Mannose / Q000737:chemistry; D010330:Patents as Topic; D013329:Structure-Activity Relationship; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D008358:Mannose
keywords: Crohn’s disease; E. coli bacteria; FimH; carbohydrate; gram-negative; lectin; mannoside; type 1 pili; urinary tract infection; virulence factor