Acylhomoserine lactone synthase inhibitors mimicking the enzyme reaction intermediate

细菌使用一种称为群体感应(QS)的细胞间通信机制，以细胞群体依赖的方式调节基因表达。在革兰氏阴性菌中最常见的QS信号是N-酰基高丝氨酸内酯，它是由酰基载体蛋白和S腺苷蛋氨酸在N-酰基高丝氨酸内酯合成酶的催化下合成的。尽管人们对控制细菌QS有相当大的兴趣，但仍然没有有效的关键酶抑制剂。在这里，我们报道了一类新的AHL合成酶抑制剂，它们是基于AHL合成酶的有效反应中间体N-酰基-SAM的结构而设计的。植物病原菌Burkholderia glumae的AHL合成酶TOFI由辛酰-ACP和SAM合成N-辛酰高丝氨酸内酯(C8-HSL)，该反应被N-辛酰-SAM类似物抑制。通过对类似物结构的简化和优化，得到了具有较高抑制活性的化合物。目前的TOFI抑制剂可以是种子化合物或先导化合物，用于设计一类新的QS猝灭剂。

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.