title: A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131.
abstract: BACKGROUND
  Escherichia coli O25b:H4-ST131 represents a predominant clone of multidrug-resistant uropathogens currently circulating worldwide in hospitals and the community. Urinary tract infections (UTIs) caused by E. coli ST131 are typically associated with limited treatment options and are often recurrent.
  
  
  METHODS
  Using established mouse models of acute and chronic UTI, we mapped the pathogenic trajectory of the reference E. coli ST131 UTI isolate, strain EC958.
  
  
  RESULTS
  We demonstrated that E. coli EC958 can invade bladder epithelial cells and form intracellular bacterial communities early during acute UTI. Moreover, E. coli EC958 persisted in the bladder and established chronic UTI. Prophylactic antibiotic administration failed to prevent E. coli EC958-mediated UTI. However, 1 oral dose of a small-molecular-weight compound that inhibits FimH, the type 1 fimbriae adhesin, significantly reduced bacterial colonization of the bladder and prevented acute UTI. Treatment of chronically infected mice with the same FimH inhibitor lowered their bladder bacterial burden by >1000-fold.
  
  
  CONCLUSIONS
  In this study, we provide novel insight into the pathogenic mechanisms used by the globally disseminated E. coli ST131 clone during acute and chronic UTI and establish the potential of FimH inhibitors as an alternative treatment against multidrug-resistant E. coli.
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia.
authors.forename: Makrina
authors.initials: M
authors.lastname: Totsika
authors.forename: Maria
authors.initials: M
authors.lastname: Kostakioti
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hannan
authors.forename: Mathew
authors.initials: M
authors.lastname: Upton
authors.forename: Scott A
authors.initials: SA
authors.lastname: Beatson
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schembri
mesh_terms: D000208:Acute Disease; D018830:Adhesins, Escherichia coli; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002908:Chronic Disease; D003556:Cystitis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D010861:Fimbriae, Bacterial / Q000187:drug effects; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D001743:Urinary Bladder / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000302:isolation & purification*
chemical_list: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; C058769:fimH protein, E coli; D036781:Fimbriae Proteins
keywords: E. coli ST131; antibiotic resistance; biofilm; mannoside; type 1 fimbriae; urinary tract infection; uropathogenic E. coli