Antagonism of Quorum Sensing Phenotypes by Analogs of the Marine Bacterial Secondary Metabolite 3-Methyl-N-(2′-Phenylethyl)-Butyramide

Abstract

Quorum sensing (QS) antagonists have been proposed as novel therapeutic agents to combat bacterial infections. We previously reported that the secondary metabolite 3-methyl-<i>N</i>-(2'-phenylethyl)-butyramide, produced by a marine bacterium identified as <i>Halobacillus</i> <i>salinus</i>, inhibits QS controlled phenotypes in multiple Gram-negative reporter strains. Here we report that <i>N</i>-phenethyl hexanamide, a structurally-related compound produced by the marine bacterium <i>Vibrio</i> <i>neptunius</i>, similarly demonstrates QS inhibitory properties. To more fully explore structure-activity relationships within this new class of QS inhibitors, a panel of twenty analogs was synthesized and biologically evaluated. Several compounds were identified with increased attenuation of QS-regulated phenotypes, most notably <i>N</i>-(4-fluorophenyl)-3-phenylpropanamide against the marine pathogen <i>Vibrio harveyi</i> (IC₅₀ = 1.1 µM). These findings support the opportunity to further develop substituted phenethylamides as QS inhibitors.