title: Non-antibiotic quorum sensing inhibitors acting against N-acyl homoserine lactone synthase as druggable target.
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.
authors.affiliation: 1] Interdisciplinary Computing and Complex BioSystems (ICOS) research group, School of Computing Science, Claremont Tower, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK [2] The Centre for Bacterial Cell Biology, Medical School, Newcastle University, Richardson Road, Newcastle upon Tyne, NE2 4AX, UK.
authors.forename: Chien-Yi
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Thiba
authors.initials: T
authors.lastname: Krishnan
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Wai-Fong
authors.initials: WF
authors.lastname: Yin
authors.affiliation: Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Yee-Meng
authors.initials: YM
authors.lastname: Chong
authors.affiliation: Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Li Ying
authors.initials: LY
authors.lastname: Tan
authors.affiliation: Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Teik Min
authors.initials: TM
authors.lastname: Chong
authors.affiliation: Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Kok-Gan
authors.initials: KG
authors.lastname: Chan
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D018441:Biofilms / Q000187:drug effects; D015374:Biosensing Techniques / Q000379:methods; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D008025:Ligases / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects*; D020156:Salicylic Acid / Q000378:metabolism; D013634:Tannins / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013634:Tannins; D037521:Virulence Factors; C088386:homoserine lactone; D008025:Ligases; C449816:N-acylhomoserine lactone synthase; D020156:Salicylic Acid; D015107:4-Butyrolactone