Small Molecule Inhibitors of Bacterial Quorum Sensing ^†

Abstract

Quorum sensing is a bacterial mechanism that is essential in the pathogenesis of many infections, such as P. aeruginosa. These infections are strongly influenced by specific quorum sensing molecules, such as Autoinducer-2 (AI-2). AI-2 binds to quorum sensing receptors within bacteria, leading to the up-regulation of virulence genes that cause biofilm formation and toxin production. Naturally-occurring brominated furanones isolated from the marine algae Delisea pulchra were previously found to possess properties which inhibited bacterial quorum sensing in AI-2 sensitive species. The aim of this work was to create a series of novel halogenated furanones which can function as quorum sensing inhibitors of AI-2. Based on the lead from Delisea pulchra, a library of compounds was synthesised via the functionalisation of gem-dibromoolefin and gem-dichloroolefin intermediates using palladium-catalysed couplings, namely Suzuki and Sonogashira reactions. These compounds were subsequently evaluated for their effects on biofilm formation in selected microbes. Several molecules were confirmed to be highly effective biofilm inhibitors in multiple pathogens, including P. aeruginosa and C. albicans.