Development of inhibitors against TraR quorum-sensing system in Agrobacterium tumefaciens by molecular modeling of the ligand-receptor interaction.
The quorum sensing (QS) inhibitors that antagonize TraR, a receptor protein for N-3-oxo-octanoyl-L-homoserine lactones (3-oxo-C8-HSL), a QS signal of Agrobacterium tumefaciens were developed. The structural analogues of 3-oxo-C8-HSL were designed by in silico molecular modeling using SYBYL packages, and synthesized by the solid phase organic synthesis (SPOS) method, where the carboxamide bond of 3-oxo-C8-HSL was replaced with a nicotinamide or a sulfonamide bond to make derivatives of N-nicotinyl-L-homoserine lactones or N-sulfonyl-L-homoserine lactones. The in vivo inhibitory activities of these compounds against QS signaling were assayed using reporter systems and compared with the estimated binding energies from the modeling study. This comparison showed fairly good correlation, suggesting that the in silico interpretation of ligand-receptor structures can be a valuable tool for the pre-design of better competitive inhibitors. In addition, these inhibitors also showed anti-biofilm activities against Pseudomonas aeruginosa.
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA.
Cheoljin
C
Kim
Jaeeun
J
Kim
Hyung-Yeon
HY
Park
Hee-Jin
HJ
Park
Chan Kyung
CK
Kim
Jeyong
J
Yoon
Joon-Hee
JH
Lee
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016960:Agrobacterium tumefaciens / Q000378:metabolism*; D001422:Bacterial Adhesion / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D057219:Biofouling; D001681:Biological Assay / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D011550:Pseudomonas aeruginosa / Q000166:cytology / Q000187:drug effects; D053038:Quorum Sensing / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D013816:Thermodynamics
D001426:Bacterial Proteins; D008024:Ligands; D011956:Receptors, Cell Surface; C080512:TraR protein, Agrobacterium tumefaciens; C088386:homoserine lactone; D015107:4-Butyrolactone