Tailor-made LasR agonists modulate quorum sensing in Pseudomonas aeruginosa.
The primary quorum sensing system in the opportunistic pathogen Pseudomonas aeruginosa is regulated through the synthesis and secretion of N-3-oxo-dodecanoyl-L-homoserine lactone (C12) which binds the transcriptional activator LasR. In this study we report the design, synthesis and biological evaluation of new analogs of C12. Analysis of the autoinducer binding site cavity of LasR revealed a positively charged cavity near the center of bound C12. Accordingly, we synthesized two piperidine-C12 diastereoisomers and tested their biological activity. Both analogs proved to be strong LasR agonists that showed a synergistic effect when presented together with the natural ligand. Moreover, binding of the analogs resulted in phenotypic changes characteristic of QS controlled receptor activation.
Department of Chemistry and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel. meijler@bgu.ac.il.
Nira
N
Rabin
Antonia
A
Delago
Boaz
B
Inbal
Pnina
P
Krief
Michael M
MM
Meijler
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000819:agonists*; D004305:Dose-Response Relationship, Drug; D006714:Homoserine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D053038:Quorum Sensing / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000819:agonists*
D001426:Bacterial Proteins; C080365:LasR protein, Pseudomonas aeruginosa; C109860:N-(3-oxododecanoyl)homoserine lactone; D015534:Trans-Activators; D006714:Homoserine; D015107:4-Butyrolactone