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

Susan M Meschwitz,Ann Mozzer,Margaret E Teasdale,Stephanie Forschner-Dancause,Jiayuan Liu,Nicole Martin,David C Rowley

doi:10.3390/md17070389

Susan M Meschwitz, Ann Mozzer + Show 5 more

Open Access

https://doi.org/10.3390/md17070389

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Journal: Marine Drugs	Publication Date: Jul 1, 2019
Citations: 9	License type: CC BY 4.0

Affiliation: Salve Regina University, University of Rhode Island

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-N-(2′-phenylethyl)-butyramide, produced by a marine bacterium identified as Halobacillus salinus, inhibits QS controlled phenotypes in multiple Gram-negative reporter strains. Here we report that N-phenethyl hexanamide, a structurally-related compound produced by the marine bacterium Vibrio neptunius, 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 N-(4-fluorophenyl)-3-phenylpropanamide against the marine pathogen Vibrio harveyi (IC50 = 1.1 µM). These findings support the opportunity to further develop substituted phenethylamides as QS inhibitors.

Highlights

Bacterial populations synchronize gene expression via the release, detection, and biochemical response to small signaling molecules called autoinducers [1,2]
We previously reported that phenethylamide phenethylamide secondary secondary metabolites metabolites
This is the first secondary metabolite reported for this bacteria species

Summary

Introduction

Bacterial populations synchronize gene expression via the release, detection, and biochemical response to small signaling molecules called autoinducers [1,2]. In the case of pathogenic bacteria, this chemical communication process, referred to as quorum sensing (QS), coordinates phenotypes such as production of virulence factors, biofilms, and swarming motility [3,4,5,6,7]. Interference with QS pathways provides an opportunity to attenuate pathogenicity, thereby representing a novel mechanism for battling bacterial infections [8,9,10,11]. Natural product investigations have yielded structurally distinct quorum sensing inhibitors (QSIs), such as the brominated furanones isolated from the marine red alga Delisea pulchra [14,15]. Synthetic modifications to many of these naturally-occurring scaffolds have led to higher affinity antagonists against bacteria pathogens [18]

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