Synthetic Multimeric Heptyl Mannosides as Potent Antiadhesives of Uropathogenic Escherichia coli
Synthetic Multimeric Heptyl Mannosides as Potent Antiadhesives of Uropathogenic Escherichia coli
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DOI：
10.1002/cmdc.200900034
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发表时间：
2009-05-01
期刊：
影响因子：
3.4
通讯作者：
Kovensky, Jose
中科院分区：
文献类型：
--
作者：
Gouin, Sebastien G.;Wellens, Adinda;Kovensky, Jose
尿路感染引起的尿路致病性大肠杆菌提出了一个严重的社区和医院的健康问题，细菌粘附到膀胱细胞启动。大肠杆菌表达的菌毛顶端有一个结合甘露糖的粘附素FimH。庚基α-D-甘露糖苷（HM）是这种凝集素的纳摩尔抑制剂，可防止1型纤毛E.大肠杆菌和降低细菌水平的小鼠膀胱炎模型。在此，我们描述了铜催化叠氮炔环加成（CuAAC）的多聚庚基甘露糖苷的化合价范围从1到4的合成。多价化合物的生物学评估显示，与HM相比，效力有所增加。膀胱细胞结合的抑制突出了一种有前途的四价衍生物，其抑制浓度分别比甘露糖和HM低6000倍和64倍。
Urinary tract infections caused by uropathogenic Escherichia coli presents a serious communal and nosocomial health problem initiated by bacterial adhesion to the bladder cells. E coli expresses fimbriae with a mannose-binding adhesin, FimH, at the tip. Heptyl alpha-D-mannoside (HM) is a nanomolar inhibitor of this lectin, preventing adhesion of type 1-piliated E. coli and reducing bacteria levels in a murine cystitis model. Herein, we described the synthesis of multimeric heptyl-mannosides with valencies ranging from one to four by copper-catalyzed azide alkyne cycloaddition (CuAAC). Biological evaluation of the multivalent compounds revealed an increase in potency compared to HM. Inhibition of bladder cell binding highlighted a promising tetravalent derivative with inhibitory concentrations 6000-and 64-fold lower than mannose and HM respectively.