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Gemma L Thomas

Publications and source records attributed to Gemma L Thomas.

7 recordsLinked to original sources
PubMed2006

Immunomodulatory effects of Pseudomonas aeruginosa quorum sensing small molecule probes on mammalian macrophages.

Pseudomonas aeruginosa produces the quorum sensing signalling molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). This natural product not only coordinates production of virulence factors by the bacterium, but also has immunomodulatory effects on the host organism. Immunomodulatory small molecules are valuable for immunology research and are potential therapeutics for autoimmune diseases such as rheumatoid arthritis, and immunosuppressive drugs following organ transplants. We describe the total synthesis of OdDHL using solid-supported reagents and scavengers, which has the potential to be used for automated analogue synthesis. OdDHL and four analogues were tested for their ability to activate or inhibit release of the pro-inflammatory mediators tumour necrosis factor alpha (TNFalpha) and nitric oxide (NO) from equine or murine macrophages (immune cells). Two of the analogues showed substantial immunomodulatory activity with these macrophages. One analogue showed differing species selectivity, being a potent antagonist in mouse cells, but a partial agonist in horse-derived macrophages. These compounds have the therapeutic potential to be used for protecting animals from bacterial septic shock.

4-Butyrolactone↗
PubMed2006

Enriching chemical space with diversity-oriented synthesis.

The search for new molecular entities in drug discovery and chemical genetic programs requires the screening of high-quality collections of structurally diverse small molecules. The design and synthesis of such collections remains a major challenge to synthetic chemists. Recent strategies and results are presented in the context of the chemical space being interrogated.

Combinatorial Chemistry Techniques↗
PubMed2005

Structure-activity relationships of Erwinia carotovora quorum sensing signaling molecules.

Production of virulence factors and secondary metabolites is regulated in the phytopathogen Erwinia carotovora by quorum sensing involving N-acylated homoserine lactone (AHL) signaling molecules. Non-hydrolyzable AHL analogues were synthesized and screened in vivo. The biological activity of each compound was correlated with its ability to bind Erwinia AHL receptor proteins (LuxR homologues) in vitro. There is an excellent correlation between carbapenem production in vivo and in vitro binding to CarR. However, no such correlation could be found between exoprotease production and analogue binding to EccR. Our data are consistent with the involvement of a third, as yet uncharacterized LuxR homologue.

4-Butyrolactone↗
PubMed2005

Cell-cell communication in Gram-negative bacteria.

Over the last decade or so, a wealth of research has established that bacteria communicate with one another using small molecules. These signals enable the individuals in a population to coordinate their behaviour. In the case of pathogens, this behaviour may include decisions such as when to attack a host organism or form a biofilm. Consequently, such signalling systems are excellent targets for the development of new antibacterial therapies. In this review, we assess how Gram-negative bacteria use small molecules for cell-cell communication, and discuss the main approaches that have been developed to interfere with it.

Cell Communication↗
PubMed2004

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.

4-Butyrolactone↗
PubMed2003

Anion-directed assembly: the first fluoride-directed double helix.

The crystal structures of anion complexes of two nitroaromatic functionalised isophthalamides are reported; the structures reveal assembly around anions in the solid-state and in the case of the fluoride complex of receptor 2, the formation of a double helix.

Journal Article↗