Synthesis and Molecular Modeling Provide Insight into a Pseudomonas aeruginosa Quorum Sensing Conundrum

• Published in: Journal of the American Chemical Society 2011-03, Vol.133 (11), p.3840-3842
• Main Authors: Zakhari, Joseph S, Kinoyama, Isao, Struss, Anjali K, Pullanikat, Prasanna, Lowery, Colin A, Lardy, Matthew, Janda, Kim D
• Format: Article
• Language: English
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemical synthesis; Models, Molecular; Pseudomonas aeruginosa - physiology; Quorum Sensing
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja111138y

The triphenyl amide/ester 12 was originally reported to be a potent mimic of the natural 3-oxo-dodecanoyl homoserine lactone quorum sensing molecule in Pseudomonas aeruginosa. However, explicit synthesis/chemical characterization was lacking, and a later report providing protein crystallographic data inferred 12 to be incorrect, with 9 now being the surmised structure. Because of these inconsistencies and our interest in quorum sensing molecules utilized by Gram-negative bacteria, we found it necessary to synthesize 9 and 12 to test for agonistic activity in a P. aeruginosa reporter assay. Despite distinct regiochemical differences, both 9 and 12 were found to have comparable EC50 values. To reconcile these unanticipated findings, modeling studies were conducted, and both compounds were revealed to have comparable properties for binding to the LasR receptor.