Antibiotic Development Towards UPEC-FimH Against Urinary Tract Infections

The number of people around the world every year with Urinary Tract Infections is about 150 million and the incidence rate among women is as high as 12.6%.In the thesis,the strategy of a molecular bait was used to block the invasion of urinary tract pathogenic E.coli.That means that mannose derivatives bind the FimH protein of urinary tract pathogenic E.coli to prevent binding with human high-mannose glycoprotein.Move further,a antibiotic was developed using this strategy.The treatment of UTIs with this novel strategy has important academic significance and outstanding application value.Firstly,We focused structure-activity relationship study on the 6-position of the mannose skeleton,and the 6-position hydroxyl group is proved to be necessary.On this basis,we designed dual-target mannose small molecule synthesis,the optimal molecule HAI₉₀ is 0.12 nM.Secondly,in order to improve the stability of mannose antibiotics,we designed C-mannose whose stability is greatly improved.The best HAI₉₀ activity among molecules is 260 nM,which build up a solid basis for follow-up research.Finally,we explored the construction of sugar-amino acid skeleton using the idea of co-catalysis,which provided a route for the subsequent dihydroxylation to construct mannose analogs.