Design, Synthesis, and Evaluation of Transition-State Analogs as Inhibitors of the Bacterial Quorum Sensing Autoinducer Synthase CepI

Quorum sensing is a bacterial signaling system that involves the synthesis and subsequent detection of small signal molecules called autoinducers. The main autoinducer in gram-negative bacteria are acylated homoserine lactones (AHLs), produced by LuxI autoinducer synthase enzymes and detected by LuxR autoinducer receptors. Quorum sensing allows for changes in gene expression resulting bacterial behavior in a coordinated, cell-density dependent fashion. Some of the behaviors controlled by quorum sensing involve pathogenesis, making quorum sensing signaling a target to develop new antibacterial agents. Here we describe the design and synthesis of transition-state analogs of the autoinducer synthase enzymatic reaction and the evaluation of these compounds as inhibitors of the synthase CepI. One such compound potently inhibits CepI and constitutes a new type of inhibitor against this underdeveloped antibacterial target.