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1.
Bioorg Med Chem ; 19(16): 4820-8, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21798746

ABSTRACT

Quorum sensing (QS) is a process by which bacteria use small molecules or peptidic signals to assess their local population densities. At sufficiently high density, bacteria can alter gene expression levels to regulate group behaviors involved in a range of important and diverse phenotypes, including virulence factor production, biofilm formation, root nodulation, and bioluminescence. Gram-negative bacteria most commonly use N-acylated l-homoserine lactones (AHLs) as their QS signals. The AHL lactone ring is hydrolyzed relatively rapidly at biological pH, and the ring-opened product is QS inactive. We seek to identify AHL analogues with heightened hydrolytic stability, and thereby potentially heightened activity, for use as non-native modulators of bacterial QS. As part of this effort, we probed the utility of thiolactone analogues in the current study as QS agonists and antagonists in Gram-negative bacteria. A focused library of thiolactone analogs was designed and rapidly synthesized in solution. We examined the activity of the library as agonists and antagonists of LuxR-type QS receptors in Pseudomonas aeruginosa (LasR), Vibrio fischeri (LuxR), and Agrobacterium tumefaciens (TraR) using bacterial reporter strains. The thiolactone library contained several highly active compounds, including some of the most active LuxR inhibitors and the most active synthetic TraR agonist reported to date. Analysis of a representative thiolactone analog revealed that its hydrolysis half-life was almost double that of its parent AHL in bacterial growth medium.


Subject(s)
Acyl-Butyrolactones/chemical synthesis , Gram-Negative Bacteria/drug effects , Pseudomonas aeruginosa/drug effects , Quorum Sensing/drug effects , Repressor Proteins/drug effects , Trans-Activators/drug effects , Acetylation , Acyl-Butyrolactones/chemistry , Acyl-Butyrolactones/pharmacokinetics , Acyl-Butyrolactones/pharmacology , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Genes, Reporter/drug effects , Gram-Negative Bacteria/genetics , Gram-Negative Bacteria/metabolism , Hydrolysis , Molecular Targeted Therapy , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/metabolism , Quorum Sensing/physiology , Repressor Proteins/agonists , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/physiology , Trans-Activators/agonists , Trans-Activators/antagonists & inhibitors , Trans-Activators/physiology
2.
Anal Bioanal Chem ; 389(5): 1447-57, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17899036

ABSTRACT

Bacterial intraspecies and interspecies communication in the rhizosphere is mediated by diffusible signal molecules. Many Gram-negative bacteria use N-acyl-homoserine lactones (AHLs) as autoinducers in the quorum sensing response. While bacterial signalling is well described, the fate of AHLs in contact with plants is much less known. Thus, adsorption, uptake and translocation of N-hexanoyl- (C6-HSL), N-octanoyl- (C8-HSL) and N-decanoyl-homoserine lactone (C10-HSL) were studied in axenic systems with barley (Hordeum vulgare L.) and the legume yam bean (Pachyrhizus erosus (L.) Urban) as model plants using ultra-performance liquid chromatography (UPLC), Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and tritium-labelled AHLs. Decreases in AHL concentration due to abiotic adsorption or degradation were tolerable under the experimental conditions. The presence of plants enhanced AHL decline in media depending on the compounds' lipophilicity, whereby the legume caused stronger AHL decrease than barley. All tested AHLs were traceable in root extracts of both plants. While all AHLs except C10-HSL were detectable in barley shoots, only C6-HSL was found in shoots of yam bean. Furthermore, tritium-labelled AHLs were used to determine short-term uptake kinetics. Chiral separation by GC-MS revealed that both plants discriminated D-AHL stereoisomers to different extents. These results indicate substantial differences in uptake and degradation of different AHLs in the plants tested.


Subject(s)
Acyl-Butyrolactones/metabolism , Plants/metabolism , Acyl-Butyrolactones/pharmacokinetics , Hordeum/metabolism , Pachyrhizus/metabolism , Quorum Sensing , Stereoisomerism , Tandem Mass Spectrometry/methods , Tritium
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