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.

A number of bacteria, including some significant pathogens, utilize N-acylhomoserine lactones (AHLs) as quorum sensing signals. There is considerable interest in the therapeutic potential of disrupting quorum sensing. Recently, a number of bacteria have been identified which are capable of enzymic inactivation of AHLs. These enzymes show considerable promise as 'quenchers' of quorum sensing. However, the assumption that the natural function of these enzymes is to disrupt or modulate quorum sensing has yet to be established. This review surveys the progress made to date in this field and examines what implications these findings have for our understanding of the role played by these enzymes in vivo.

Beating the superbugs: Diversity‐oriented synthesis using a solid‐supported phosphonate unit to synthesize 242 drug‐like compounds based on 18 natural‐product‐like scaffolds led to the discovery of gemmacin (see scheme). This new structural class of antibiotic is active towards methicillin‐resistant Staphylococcus aureus (MRSA).

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.

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