Induction and inhibition of Pseudomonas aeruginosa quorum sensing by synthetic autoinducer analogs.
We synthesized a library of Pseudomonas aeruginosa autoinducer analogs with variation targeted to the homoserine lactone (HSL) moiety and discovered a new agonist, 3-oxo-C(12)-(2-aminocyclohexanol), capable of activating LasR as a transcription factor. We reconstructed two sets of focused libraries against the quorum-sensing transcription factors LasR and RhlR, respectively. Opposing the prediction that both proteins should have the same binding site for HSL, it was surprising to find that these two related proteins respond to different structural motifs. This suggests that the HSL binding site differs in these proteins. We also found that subtle structural modifications to the agonists yielded compounds with antagonist activity. We performed a series of assays to show that inhibition of quorum sensing by these antagonists significantly reduced the production of virulence factors and biofilm formation.
Smith
Kristina M
KM
Department of Biological Sciences, University at Buffalo, State University of New York, 14260, USA.
Bu
Yigong
Y
Suga
Hiroaki
H
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D025461:Feedback, Physiological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D046911:Macromolecular Substances; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D037521:Virulence Factors / Q000037:antagonists & inhibitors
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C080365:LasR protein, Pseudomonas aeruginosa; D046911:Macromolecular Substances; C086515:RhlR protein, Pseudomonas aeruginosa; D015534:Trans-Activators; D037521:Virulence Factors; C088386:homoserine lactone; D015107:4-Butyrolactone