Substituted lactam and cyclic azahemiacetals modulate Pseudomonas aeruginosa quorum sensing

Venkata L A Malladi, Adam J. Sobczak, Natalie Maricic, Senthil Kumar Murugapiran, Lisa Schneper, John Makemson, Kalai Mathee, Stanislaw F. Wnuk

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Quorum sensing (QS) is a population-dependent signaling process bacteria use to control multiple processes including virulence that is critical for establishing infection. The most common QS signaling molecule used by Gram-negative bacteria are acylhomoserine lactones. The development of non-native acylhomoserine lactone (AHL) ligands has emerged as a promising new strategy to inhibit QS in Gram-negative bacteria. In this work, we have synthesized a set of optically pure γ-lactams and their reduced cyclic azahemiacetal analogues, bearing the additional alkylthiomethyl substituent, and evaluated their effect on the AHL-dependent Pseudomonas aeruginosa las and rhl QS pathways. The concentration of these ligands and the simple structural modification such as the length of the alkylthio substituent has notable effect on activity. The γ-lactam derivatives with nonylthio or dodecylthio chains acted as inhibitors of las signaling with moderate potency. The cyclic azahemiacetal with shorter propylthio or hexylthio substituent was found to strongly inhibit both las and rhl signaling at higher concentrations while the propylthio analogue strongly stimulated the las QS system at lower concentrations.

Original languageEnglish (US)
Pages (from-to)5500-5506
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number18
DOIs
StatePublished - Sep 15 2011

Bibliographical note

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

Keywords

  • Azahemiacetals
  • Azasugars
  • Pseudomonas aeruginosa
  • Quorum sensing

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