Hydroxychalcone inhibitors of Streptococcus mutans glucosyl transferases and biofilms as potential anticaries agents
| Autor: | Sadanandan E. Velu, Ruowen Zheng, Bhavitavya Nijampatnam, Luke Casals, Hui Wu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
030106 microbiology Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests Biochemistry Article Microbiology Streptococcus mutans Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Flavonols Glucosyltransferases Drug Discovery Molecular Biology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry Biofilm Streptococcus gordonii biochemical phenomena metabolism and nutrition biology.organism_classification Anti-Bacterial Agents Streptococcus sanguinis 030104 developmental biology Enzyme chemistry Biofilms Molecular Medicine Lead compound |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:3508-3513 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.06.033 |
| Popis: | Streptococcus mutans has been implicated as the major etiological agent in the initiation and the development of dental caries due to its robust capacity to form tenacious biofilms. Ideal therapeutics for this disease will aim to selectively inhibit the biofilm formation process while preserving the natural bacterial flora of the mouth. Several studies have demonstrated the efficacies of flavonols on S. mutans biofilms and have suggested the mechanism of action through their effect on S. mutans glucosyltransferases (Gtfs). These enzymes metabolize sucrose into water insoluble and soluble glucans, which are an integral measure of the dental caries pathogenesis. Numerous studies have shown that flavonols and polyphenols can inhibit Gtf and biofilm formation at millimolar concentrations. We have screened a group of 14 hydroxychalcones, synthetic precursors of flavonols, in an S. mutans biofilm assay. Several of these compounds emerged to be biofilm inhibitors at low micro-molar concentrations. Chalcones that contained a 3-OH group on ring A exhibited selectivity for biofilm inhibition. Moreover, we synthesized 6 additional analogs of the lead compound and evaluated their potential activity and selectivity against S. mutans biofilms. The most active compound identified from these studies had an IC50 value of 44µM against biofilm and MIC50 value of 468µM against growth displaying >10 fold selectivity inhibition towards biofilm. The lead compound displayed a dose dependent inhibition of S. mutans Gtfs. The lead compound also did not affect the growth of two commensal species (Streptococcus sanguinis and Streptococcus gordonii) at least up to 200 µM, indicating that it can selectively inhibit cariogenic biofilms, while leaving commensal and/or beneficial microbes intact. Thus non-toxic compounds have the potential utility in public oral health regimes. |
| Databáze: | OpenAIRE |
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