Silyl-Lipid Functionalized <i>N</i>-Acyl Homoserine Lactones as Modulators of Bacterial Cell–Cell Communication

We report silyl-lipid derivatives of <i>N</i>-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 <i>Pseudomonas aeruginosa</i> using <i>E. coli</i> reporter gene assays. Several silyl-lipid AHL agonists retained high activities in LasR in a native <i>P. aeruginosa</i> reporter system and also were active in another related LuxR-type receptor, EsaR from <i>Pantoea stewartii</i>. 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.