Qin, X, Thota, GK, Singh, R et al. (2 more authors) (2020) Synthetic homoserine lactone analogues as antagonists of bacterial quorum sensing. Bioorganic Chemistry, 98. 103698. ISSN 0045-2068
Abstract
Quorum sensing (QS) is a density-dependent form of cell-cell communication that triggers the functional coordination of cooperative behaviors such as the production of virulence factors and biofilm formation. Quorum quenching (QQ) refers to all processes involved in the disruption of QS and is regarded as a promising strategy for treating bacterial infections. Herein, four compounds with closely related chemical structures to homoserine γ-lactone were synthesized and fully characterized. The compounds are termed TGK-series compounds. These compounds were subsequently tested in their QS inhibition activity using an E. coli Top 10 QS biosensor strain, a GFP QS reporter, that probes the capacity of bacteria to detect their cognate autoinducer N-(3-oxohexanoyl)-homoserine lactone (3OC6HSL) substrate by means of a single intracellular protein LuxR. All TGK-series compounds were found to significantly inhibit the ability of bacteria to produce GFP but without exerting toxicity when applied at a concentration of 50 µM. In parallel, the interaction of TGK-series compounds with LuxR were studied by molecular docking simulations. These studies revealed that TGK-series compounds bound to the natural substrate N-(3-oxo-octanoyl)-l-homoserine lactone (OOHL) binding site and that the binding ability of the compounds with the TraR protein (a surrogate of LuxR) was even more favorable in comparison with the natural substrate. It was also uncovered that TGK-series compounds form stronger hydrophobic interactions with the TraR protein than 3OC6HSL does, thus providing a rationale for the enhancement of the QQ activity of the synthetic TGK-series compounds. This study will serve to guide future works aimed to design promising novel QS inhibitor candidates on a rational basis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Keywords: | Quorum sensing; TGK-series compounds; Molecular docking; Hydrophobic interaction; Quorum quenching |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Environment (Leeds) > School of Food Science and Nutrition (Leeds) > FSN Chemistry and Biochemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Feb 2021 10:53 |
Last Modified: | 11 Feb 2021 10:53 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.bioorg.2020.103698 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:170831 |