Synthesis and stability of small molecule probes for Pseudomonas aeruginosa quorum sensing modulation.
The human pathogen Pseudomonas aeruginosa uses N-butyryl-L-homoserine lactone (BHL) and N-(3-oxododecanyl)-L-homoserine lactone (OdDHL) as small molecule intercellular signals in a phenomenon known as quorum sensing (QS). QS modulators are effective at attenuating P. aeruginosa virulence; therefore, they are a potential new class of antibacterial agent. The lactone in BHL and OdDHL is hydrolysed under physiological conditions. The hydrolysis proceeds at a rate faster than racemisation of the alpha-chiral centre. Non-hydrolysable, non-racemic analogues (small molecule probes) were designed and synthesised, replacing the lactone with a ketone. OdDHL analogues were found to be relatively unstable to decomposition unless they were difluorinated between the beta-keto amide. Stability studies on a non-hydrolysable, cyclohexanone analogue indicated that racemisation of the alpha-chiral centre was relatively slow. This analogue was assayed to show that the L-isomer is likely to be responsible for the QS autoinducing activity in P. aeruginosa and Serratia strain ATCC39006.
Glansdorp
Freija G
FG
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Thomas
Gemma L
GL
Lee
Jungjoon K
JK
Dutton
Jenny M
JM
Salmond
George P C
GP
Welch
Martin
M
Spring
David R
DR
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D001671:Biochemistry / Q000379:methods*; D003512:Cyclohexanones / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005461:Fluorine / Q000737:chemistry; D006714:Homoserine / Q000031:analogs & derivatives / Q000737:chemistry; D006868:Hydrolysis; D007536:Isomerism; D007659:Ketones / Q000737:chemistry; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity / Q000502:physiology*; D012705:Serratia / Q000502:physiology; D013329:Structure-Activity Relationship
D003512:Cyclohexanones; D007659:Ketones; D015335:Molecular Probes; C109860:N-(3-oxododecanoyl)homoserine lactone; C092312:N-butyrylhomoserine lactone; D005461:Fluorine; C036468:cyclohexanone; D006714:Homoserine; D015107:4-Butyrolactone