Non-antibiotic quorum sensing inhibitors acting against N-acyl homoserine lactone synthase as druggable target

Citations Over TimeTop 10% of 2014 papers

Abstract

N-acylhomoserine lactone (AHL)-based quorum sensing (QS) is important for the regulation of proteobacterial virulence determinants. Thus, the inhibition of AHL synthases offers non-antibiotics-based therapeutic potentials against QS-mediated bacterial infections. In this work, functional AHL synthases of Pseudomonas aeruginosa LasI and RhlI were heterologously expressed in an AHL-negative Escherichia coli followed by assessments on their AHLs production using AHL biosensors and high resolution liquid chromatography-mass spectrometry (LCMS). These AHL-producing E. coli served as tools for screening AHL synthase inhibitors. Based on a campaign of screening synthetic molecules and natural products using our approach, three strongest inhibitors namely are salicylic acid, tannic acid and trans-cinnamaldehyde have been identified. LCMS analysis further confirmed tannic acid and trans-cinnemaldehyde efficiently inhibited AHL production by RhlI. We further demonstrated the application of trans-cinnemaldehyde inhibiting Rhl QS system regulated pyocyanin production in P. aeruginosa up to 42.06%. Molecular docking analysis suggested that trans-cinnemaldehyde binds to the LasI and EsaI with known structures mainly interacting with their substrate binding sites. Our data suggested a new class of QS-inhibiting agents from natural products targeting AHL synthase and provided a potential approach for facilitating the discovery of anti-QS signal synthesis as basis of novel anti-infective approach.

Related Papers

• → Silencing Quorum Sensing through Extracts of Melicope lunu-ankenda(2012)65 cited
• → Inhibition of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells by quorum sensing autoinducer-mimics(2012)77 cited
• → Potent Irreversible Inhibitors of LasR Quorum Sensing in Pseudomonas aeruginosa(2014)60 cited
• Natural compounds targeting pyocyanin and quorum sensing in Pseudomonas aeruginosa(2018)
• → Anti-quorum Sensing Potential of Ageratum Conyzoides L. (Asteraceae) Extracts(2021)