Quorum sensing in Gram-negative bacteria: small-molecule modulation of AHL and AI-2 quorum sensing pathways.

Numerous species of bacteria employ a mechanism of intercellular communication known as quorum sensing. This signaling process allows the cells comprising a bacterial colony to coordinate their gene expression in a cell-density dependent manner.1-3 Quorum sensing is mediated by small diffusible molecules termed autoinducers that are synthesized intracellularly (throughout the growth of the bacteria) and released into the surrounding milieu. As the number of cells in a bacterial colony increases, so does the extracellular concentration of the autoinducer. Once a threshold concentration is reached (at which point the population is considered to be “quorate”), productive binding of the autoinducer to cognate receptors within the bacterial cells occurs, triggering a signal transduction cascade that results in population-wide changes in gene expression.4-6 Thus, quorum sensing enables the cells within a bacterial colony to act cooperatively, facilitating population-dependent adaptive behavior.6 Quorum sensing has been shown to play a critical role in both pathogenic and symbiotic bacteria-host interactions.5 In symbionts, significant quorum sensing phenotypes include bioluminescence and root nodulation.7-11 Several clinically relevant pathogens use quorum sensing systems to regulate processes associated with virulence; this enhances the survival prospects of the bacteria because a coordinated attack on the host is only made when the bacterial population reaches a high population density, increasing the likelihood that the hosts defenses will be successfully overwhelmed.12,13 For example, in Pseudomonas aeruginosa, quorum sensing is involved in the formation of biofilms and their tolerance to antimicrobial agents14-17 and the innate host immune * To whom correspondence should be addressed. Tel.: +44 (0)1223 336498. Fax: +44 (0)1223 336362. E-mail: [email protected]. † Department of Chemistry. ‡ Department of Biochemistry. Chem. Rev. 2011, 111, 28–67 28