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

• Published in: Bioorganic & medicinal chemistry 2012-05, Vol.20 (9), p.3128-3142
• Main Authors: Chorell, Erik, Pinkner, Jerome S., Bengtsson, Christoffer, Banchelin, Thomas Sainte-Luce, Edvinsson, Sofie, Linusson, Anna, Hultgren, Scott J., Almqvist, Fredrik
• Format: Article
• Language: English
• Subjects: 2-Pyridone; Alga Chlamydomonas-ReinhardTII; Antenna Proteins; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antivirulence; Arabidopsis-Thaliana; biofilm; Biofilm inhibitor; Biofilms; Biofilms - drug effects; Biological and medical sciences; CAB-like proteins; Discriminant Analysis; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - physiology; fimbriae; Fimbriae, Bacterial - drug effects; Gene Family; Inducible Protein; least squares; Lipophilic; Mapping; Medical sciences; Peptidomimetic; Pharmacology. Drug treatments; Pigment-Binding Protein; Pili; Pilicide; Plant Photosystem-I; Polarity; prediction; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Quantitative Structure-Activity Relationship; quantitative structure-activity relationships; State Transitions; Structure-activity relationships; Structure–activity; Synechocystis-sp PCC-6803
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2012.01.048

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 400nM.