Antiadhesion Therapy for Urinary Tract Infections鈥擜 Balanced PK/PD Profile Proved To Be Key for Success

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• 作者：Xiaohua Jiang ; Daniela Abgottspon ; Simon Kleeb ; Said Rabbani ; Meike Scharenberg ; Matthias Wittwer ; Martina Haug ; Oliver Schwardt ; Beat Ernst
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4700-4713
• 全文大小：625K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

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 渭g/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).