(2R)- and (2S)- 2-hydroxy- hexanoyl and octanoyl-l-homoserine lactones: New highly potent Quorum Sensing modulators with opposite activities

Bioorg Chem. 2020 Nov:104:104307. doi: 10.1016/j.bioorg.2020.104307. Epub 2020 Sep 24.

Abstract

The synthesis and the QS modulation activity of diastereoisomerically pure 2-hydroxy-N-acyl-l-homoserine lactones (2-OH-AHLs) are unveiled. (2R)- and (2S)- 2-hydroxy-N-hexanoyl-l-homoserine lactone and 2-hydroxy-N-octanoyl-l-homoserine lactone have been identified as very potent QS agonists and antagonists on the Vibrio fischeri-quorum sensing system with opposite activities depending on the configuration of the carbon atom with the hydroxyl group. Flexible molecular docking showed that the (2R)-OH configuration in the antagonist isomer induces new hydrogen bonds with Tyr70 and Asp79, two importantly conserved residues in the LuxR protein family, while the (2S)-OH agonist configuration exhibits a binding mode comparable to the natural ligand 3-oxo-hexanoyl-l-homoserine lactone (OHHL). For the analogs with long alkyl chain 3a and 3b and aromatic analogs, all are antagonists with no effect of the configuration at C-2.

Keywords: 2-Hydroxy AHL; Flexible docking; Quorum sensing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / chemical synthesis
  • 4-Butyrolactone / chemistry
  • 4-Butyrolactone / pharmacology
  • Aliivibrio fischeri / drug effects*
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Escherichia coli / drug effects*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Quorum Sensing / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • homoserine lactone
  • 4-Butyrolactone