A comparative study of non-native N -acyl l -homoserine lactone analogs in two Pseudomonas aeruginosa quorum sensing receptors that share a common native ligand yet inversely regulate virulence

Abstract

<p class="first" id="P1">Certain bacteria can coordinate group behaviors via a chemical communication system known as quorum sensing (QS). Gram-negative bacteria typically use <i>N</i>-acyl L-homoserine lactone (AHL) signals and their cognate intracellular LuxR-type receptors for QS. The opportunistic pathogen <i>Pseudomonas aeruginosa</i> has a relatively complex QS circuit in which two of its LuxR-type receptors, LasR and QscR, are activated by the same natural signal, <i>N</i>-(3-oxo)-dodecanoyl L-homoserine lactone. Intriguingly, once active, LasR activates virulence pathways in <i>P. aeruginosa</i>, while activated QscR can inactivate LasR and thus repress virulence. We have a limited understanding of the structural features of AHLs that engender either agonistic activity in both receptors or receptor-selective activity. Compounds with the latter active profile could prove especially useful tools to tease out the roles of these two receptors in virulence regulation. A small collection of AHL analogues was assembled and screened in cell-based reporter assays for activity in both LasR and QscR. We identified several structural motifs that bias ligand activation towards each of the two receptors. These findings will inform the development of new synthetic ligands for LasR and QscR with improved potencies and selectivities. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/c8755ef8-a031-4ce6-87a9-dd2654f8a8cc/PubMedCentral/image/nihms969800u1.jpg"/> </div> </p>

Journal

Title: Bioorganic & Medicinal Chemistry

Abbreviated Title: Bioorganic & Medicinal Chemistry

Publisher: Elsevier BV

ISSN (Print): 09680896

Publication date Created: May 2018

Publication date (Print): May 2018

Article

DOI: 10.1016/j.bmc.2018.05.018

PMC ID: 6234094

PubMed ID: 29793752

SO-VID: 4539fdf7-dd54-45c4-b1db-070239208013

Copyright statement: © 2018

License:

https://www.elsevier.com/tdm/userlicense/1.0/

Product

Self URI (article page): https://linkinghub.elsevier.com/retrieve/pii/S0968089618305339