title: Library screening for synthetic agonists and antagonists of a Pseudomonas aeruginosa autoinducer.
abstract: The autoinducer (AI) that initiates the quorum sensing (QS) signaling cascade in Pseudomonas aeruginosa is an acyl-homoserine lactone (acyl-HSL). We initiated a study of the requirements for binding of the AI to its protein effector LasR by synthesizing a library of analogs with the HSL moiety replaced with different amines and alcohols. We tested each compound for both agonist and antagonist activity using a QS-controlled reporter gene assay and found several new agonists and antagonists. A representative antagonist was further tested for its ability to inhibit virulence factors. This data progresses our understanding of the LasR-AI interaction toward the rational design of therapeutic inhibitors of QS.
authors.affiliation: Department of Biological Sciences, State University of New York, Buffalo, Buffalo, NY 14260, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Smith
authors.forename: Yigong
authors.initials: Y
authors.lastname: Bu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000627:Aminophenols / Q000737:chemistry; D001426:Bacterial Proteins; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D015723:Gene Library; D017930:Genes, Reporter / Q000187:drug effects; D005821:Genetic Techniques; D006714:Homoserine / Q000819:agonists / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007783:Lactones / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity*; D015363:Quinolones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D037521:Virulence Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C407944:2-heptyl-3-hydroxy-4-quinolone; D000627:Aminophenols; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D007783:Lactones; C080365:LasR protein, Pseudomonas aeruginosa; C109860:N-(3-oxododecanoyl)homoserine lactone; C092312:N-butyrylhomoserine lactone; D015363:Quinolones; D015534:Trans-Activators; D037521:Virulence Factors; C085113:Pseudomonas aeruginosa autoinducer; C027667:2-aminophenol; D006714:Homoserine; D015107:4-Butyrolactone