Acylhomoserine lactone synthase inhibitors mimicking the enzyme reaction intermediate

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Bacteria employ a mechanism of intercellular communication known as quorum sensing (QS) that regulate gene expression in a cell population-dependent manner. The most common QS signals in Gram-negative bacteria are N-acylhomoserine lactones (AHLs), which are synthesized from acyl-acyl carrier protein (acyl-ACP) and S-adenosylmethionine (SAM) in a reaction catalyzed by AHL synthase. Despite considerable interest in controlling bacterial QS, there is still no efficient inhibitor of the key enzyme. Here we report a new class of AHL synthase inhibitors that were designed based on the structure of N-acyl-SAM, a potent reaction intermediate of AHL synthase. The AHL synthase TofI from the plant pathogen Burkholderia glumae produces N-octanoylhomoserine lactone (C8-HSL) from octanoyl-ACP and SAM, which reaction was inhibited by the N-octanoyl-SAM analogs. Approach of simplification and optimization of the analogs structure led to compounds with high inhibitory activity. The present TofI inhibitors can be seed or lead compounds for the design of a new class of QS quenching agents.