Design and Synthesis of Lactams Derived from Mucochloric and Mucobromic Acids as Pseudomonas aeruginosa Quorum Sensing Inhibitors

Molecules. 2018 May 7;23(5):1106. doi: 10.3390/molecules23051106.

Abstract

Bacterial infections, particularly hospital-acquired infections caused by Pseudomonas aeruginosa, have become a global threat with a high mortality rate. Gram-negative bacteria including P. aeruginosa employ N-acyl homoserine lactones (AHLs) as chemical signals to regulate the expression of pathogenic phenotypes through a mechanism called quorum sensing (QS). Recently, strategies targeting bacterial behaviour or QS have received great attention due to their ability to disarm rather than kill pathogenic bacteria, which lowers the evolutionary burden on bacteria and the risk of resistance development. In the present study, we report the design and synthesis of N-alkyl- and N-aryl 3,4 dichloro- and 3,4-dibromopyrrole-2-one derivatives through the reductive amination of mucochloric and mucobromic acid with aliphatic and aromatic amines. The quorum sensing inhibition (QSI) activity of the synthesized compounds was determined against a P. aeruginosa MH602 reporter strain. The phenolic compounds exhibited the best activity with 80% and 75% QSI at 250 µM and were comparable in activity to the positive control compound Fu-30. Computational docking studies performed using the LasR receptor protein of P. aeruginosa suggested the importance of hydrogen bonding and hydrophobic interactions for QSI.

Keywords: Pseudomonas aeruginosa; lactam; mucobromic acid; mucochloric acid; quorum sensing.

MeSH terms

  • Acyl-Butyrolactones
  • Amination
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Drug Design
  • Furans / chemistry*
  • Gene Expression
  • Lactams / chemical synthesis*
  • Lactams / pharmacology
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Oxidation-Reduction
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / metabolism
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology
  • Quorum Sensing / drug effects*
  • Structure-Activity Relationship
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Acyl-Butyrolactones
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Furans
  • Lactams
  • LasR protein, Pseudomonas aeruginosa
  • Pyrroles
  • Trans-Activators
  • mucochloric acid
  • mucobromic acid