Strategies for inhibiting quorum sensing.

The ability of bacterial cells to synchronize their behaviour through quorum sensing (QS) regulatory networks enables bacterial populations to mount co-operative responses against competing micro-organisms and host immune defences and to adapt to environmental challenges. Since QS controls the ability of many pathogenic bacteria to cause disease, it is an attractive target for novel antibacterial agents that control infection through inhibition of virulence and by rendering biofilms more susceptible to conventional antibiotics and host clearance pathways. QS systems provide multiple druggable molecular targets for inhibitors (QSIs) that include the enzymes involved in QS signal molecule biosynthesis and the receptors involved in signal transduction. Considerable advances in our understanding of the chemical biology of QS systems and their inhibition have been made, some promising QS targets structurally characterized, QSI screens devised and inhibitors identified. However, much more work is required before any QSI 'hits' with the appropriate pharmacological and pharmacokinetic properties can enter human clinical trials. Indeed, the relative efficacy of QSIs alone or as prophylactics or therapeutics or as adjuvants in combination with conventional antibiotics still needs to be extensively evaluated in vivo. Particular attention must be given to the measurement of successful QSI therapy outcomes with respect to bacterial clearance, immune response and pathophysiology. Currently, our understanding of the potential of QS as a promising antibacterial target suggests that it is likely to be of value with respect to a limited number of major pathogens.