Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study

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• 作者：Erik Chorell^a ; ^b ; Jerome S. Pinkner^b ; Christoffer Bengtsson^a ; Thomas Sainte-Luce Banchelin^a ; ^c ; Sofie Edvinsson^a ; Anna Linusson^a ; Scott J. Hultgren^b ; ^{hultgren@borcim.wustl.edu} ; Fredrik Almqvist^a ; ^c ; ^{fredrik.almqvist@chem.umu.se}
• 关键词：SAR ; structure activity relationship ; QSAR ; quantitative structure activity relationship ; PLS ; partial least squares ; OPLS-DA ; orthogonal projections to latent structures discriminant analysis ; UTI ; urinary tract infection ; SMD ; statistical molecular desi
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 May, 2012
• 卷：20
• 期：9
• 页码：3128-3142
• 文件大小：9966 K

摘要

Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study of the dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to distinguish active from inactive compounds in which polarity proved to be the most important factor for discrimination. A quantitative SAR (QSAR) partial least squares (PLS) model was calculated on the active compounds for prediction of biofilm inhibition activity. In this model, compounds with high inhibitory activity were generally larger, more lipophilic, more flexible and had a lower HOMO. Overall, this resulted in both highly valuable SAR information and potent inhibitors of type 1 pili dependent biofilm formation. The most potent biofilm inhibitor had an EC₅₀ of 400 nM.