Dolph Linnea S, Santa Emma E, Stoutland Irene M, Mesa Kelsey M, Dickson Cole C, Blackwell Helen E, Franz Annaliese K
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States.
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.
ACS Chem Biol. 2025 Feb 21;20(2):412-420. doi: 10.1021/acschembio.4c00720. Epub 2025 Feb 13.
We report silyl-lipid derivatives of -acyl l-homoserine lactones (AHLs) that have nanomolar activities in LuxR-type quorum sensing receptors in Gram-negative bacterial pathogens. A collection of silyl-lipid AHLs were designed and synthesized to represent three general structural classes based on native AHL signals and synthetic LuxR-type receptor modulators. The synthetic routes feature straightforward hydrosilylation and aryl silylation reactions to access silyl-lipid groups that are not readily accessible in analogous all-carbon chemistry. Of the 17 compounds evaluated, eight silyl-lipid AHLs were identified with either nanomolar agonistic or submicromolar antagonistic activities in the LasR receptor from the common pathogen using reporter gene assays. Several silyl-lipid AHL agonists retained high activities in LasR in a native reporter system and also were active in another related LuxR-type receptor, EsaR from . Light scattering and computational experiments indicate that the silyl-lipid group can alter the aggregation capabilities and lipophilicities of AHLs relative to native all-carbon tails, engendering larger aggregate formation in water and higher lipophilicities on average. These properties, along with their strong activity profiles in LuxR-type receptors, suggest silyl-lipid AHLs could provide value as chemical probes to study the mechanisms of quorum sensing in Gram-negative bacteria and the roles of signal lipophilicity in this chemical communication process.
我们报道了 - 酰基 - l - 高丝氨酸内酯（AHLs）的硅烷基脂质衍生物，它们在革兰氏阴性细菌病原体的LuxR型群体感应受体中具有纳摩尔活性。基于天然AHL信号和合成的LuxR型受体调节剂，设计并合成了一系列硅烷基脂质AHLs，以代表三种一般结构类型。合成路线的特点是通过直接的硅氢化反应和芳基硅烷化反应来引入硅烷基脂质基团，而这些基团在类似的全碳化学中难以获得。在评估的17种化合物中，使用报告基因测定法，在常见病原体的LasR受体中鉴定出8种硅烷基脂质AHLs具有纳摩尔激动活性或亚微摩尔拮抗活性。几种硅烷基脂质AHL激动剂在天然报告系统中的LasR中保持高活性，并且在另一种相关的LuxR型受体（来自的EsaR）中也具有活性。光散射和计算实验表明，相对于天然的全碳尾部，硅烷基脂质基团可以改变AHLs的聚集能力和亲脂性，导致在水中形成更大的聚集体，并且平均具有更高的亲脂性。这些特性，以及它们在LuxR型受体中的强活性谱，表明硅烷基脂质AHLs作为化学探针来研究革兰氏阴性细菌群体感应机制以及信号亲脂性在这种化学通讯过程中的作用可能具有价值。
