title: Antiadhesion therapy for urinary tract infections--a balanced PK/PD profile proved to be key for success.
abstract: The initial step for the successful establishment of urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli, is the adhesion of bacteria to urothelial cells. This attachment is mediated by FimH, a mannose-binding adhesin, which is expressed on the bacterial surface. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed, avoiding selection pressure and thereby implying a reduced risk of resistance. Here, we present a new class of highly active antimicrobials, targeting the virulence factor FimH. When the most potent representative, an indolinylphenyl mannoside, was administered in a mouse model at the low dosage of 1 mg/kg (corresponding to approximately 25 μg/mouse), the minimal therapeutic concentration to prevent UTI was maintained for more than 8 h. In a treatment study, the colony-forming units in the bladder could be reduced by almost 4 orders of magnitude, comparable to the standard antibiotic treatment with ciprofloxacin (8 mg/kg, sc).
authors.affiliation: Institute of Molecular Pharmacy,  University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.forename: Daniela
authors.initials: D
authors.lastname: Abgottspon
authors.forename: Simon
authors.initials: S
authors.lastname: Kleeb
authors.forename: Said
authors.initials: S
authors.lastname: Rabbani
authors.forename: Meike
authors.initials: M
authors.lastname: Scharenberg
authors.forename: Matthias
authors.initials: M
authors.lastname: Wittwer
authors.forename: Martina
authors.initials: M
authors.lastname: Haug
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D018830:Adhesins, Escherichia coli; D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001422:Bacterial Adhesion / Q000187:drug effects*; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000201:enzymology; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000382:microbiology; D008362:Mannosides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000382:microbiology; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000201:enzymology; D056689:Uropathogenic Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification; D019459:Urothelium / Q000166:cytology; D037521:Virulence Factors / Q000037:antagonists & inhibitors
chemical_list: C574762:4-(5-nitroindolin-1-yl)phenyl mannopyranoside; D018830:Adhesins, Escherichia coli; D000892:Anti-Infective Agents, Urinary; D001555:Benzene Derivatives; D007211:Indoles; D008362:Mannosides; D037521:Virulence Factors; C058769:fimH protein, E coli; D036781:Fimbriae Proteins