Structure-based discovery and experimental verification of novel Al-2 quorum sensing inhibitors against Vibrio harveyi

Quorum sensing has been implicated in the control of pathologically relevant bacterial behavior such as secretion of virulence factors, biofilm formation, sporulation, and swarming motility. The AI-2 quorum sensing pathway is found in both Gram-positive and Gram-negative bacteria. Therefore, antagonizing Al-2 quorum sensing is a possible approach to modifying bacterial behaviour. However, efforts in developing inhibitors of Al-2-mediated quorum sensing are especially lacking. High-throughput virtual screening using the V. harveyi LuxP crystal structure identified two compounds that were found to antagonize Al-2-mediated quorum sensing in V. harveyi without cytotoxicity. The sulfone functionality of these inhibitors was identified as critical to their ability to mimic the natural ligand in their interactions with Arg215 and Arg310 of the active site.