A FimH Inhibitor Prevents Acute Bladder Infection and Treats Chronic Cystitis Caused by Multidrug-Resistant Uropathogenic Escherichia coli ST131

• Published in: The Journal of infectious diseases Vol. 208; no. 6; pp. 921 - 928
• Main Authors: Totsika, Makrina, Kostakioti, Maria, Hannan, Thomas J., Upton, Mathew, Beatson, Scott A., Janetka, James W., Hultgren, Scott J., Schembri, Mark A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.09.2013
• Subjects: Acute Disease; Adhesins, Escherichia coli; Administration, Oral; Animals; Anti-Bacterial Agents - therapeutic use; Antibiotics; BACTERIA; Bacteriology; Biological and medical sciences; Bladder; Chronic Disease; Cystitis; Cystitis - drug therapy; Cystitis - microbiology; Cystitis - pathology; Disease Models, Animal; Dosage; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Escherichia coli; Female; Fimbriae; Fimbriae Proteins - antagonists & inhibitors; Fimbriae, Bacterial - drug effects; Fundamental and applied biological sciences. Psychology; Humans; Infections; Infectious diseases; Kidneys; Major and Brief Reports; Medical sciences; Mice; Mice, Inbred C3H; Microbiology; Miscellaneous; Urinary Bladder - microbiology; Urinary tract infections; Uropathogenic Escherichia coli; Uropathogenic Escherichia coli - isolation & purification; Infection; Chronic; Urinary system disease; Acute; Escherichia coli; Multiple resistance; Bacteria; Bladder disease; Urinary tract disease; Cystitis; Enterobacteriaceae; antibiotic resistance; type 1 fimbriae; biofilm; E. coli ST131; mannoside; urinary tract infection; uropathogenic E. coli
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit245

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.