TY - JOUR
T1 - Identification of LasR ligands through a virtual screening approach
AU - Skovstrup, Søren
AU - Le Quement, Sebastian Thordal
AU - Hansen, Thomas
AU - Jakobsen, Tim Holm
AU - Harmsen, Morten
AU - Tolker-Nielsen, Tim
AU - Nielsen, Thomas E
AU - Givskov, Michael
AU - Taboureau, Olivier
N1 - Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2013/1
Y1 - 2013/1
N2 - With the widespread occurrence of bacterial resistance to antibiotics, the development of new strategies beyond conventional treatments is a pursuit taken by public health institutions worldwide. LasR, a transcription factor that controls quorum sensing in Pseudomonas aeruginosa, has emerged as an attractive therapeutic target for the next generation of antimicrobial agents. In the present study, a virtual screening workflow combining pharmacophore- and structure-based approaches was used to identify new LasR ligands. Five novel inducers and three inhibitors of LasR activity were validated experimentally by use of a cell-based assay. Interestingly, these compounds are molecularly distinct from the native signal molecule, N-3-oxododecanoyl-L-homoserine lactone (OHN), and may serve as lead structures for the design of new drugs. The binding modes of these compounds to the OHN binding site in LasR were predicted and used to identify the key interactions that contribute to the induction and inhibition of LasR activity.
AB - With the widespread occurrence of bacterial resistance to antibiotics, the development of new strategies beyond conventional treatments is a pursuit taken by public health institutions worldwide. LasR, a transcription factor that controls quorum sensing in Pseudomonas aeruginosa, has emerged as an attractive therapeutic target for the next generation of antimicrobial agents. In the present study, a virtual screening workflow combining pharmacophore- and structure-based approaches was used to identify new LasR ligands. Five novel inducers and three inhibitors of LasR activity were validated experimentally by use of a cell-based assay. Interestingly, these compounds are molecularly distinct from the native signal molecule, N-3-oxododecanoyl-L-homoserine lactone (OHN), and may serve as lead structures for the design of new drugs. The binding modes of these compounds to the OHN binding site in LasR were predicted and used to identify the key interactions that contribute to the induction and inhibition of LasR activity.
U2 - 10.1002/cmdc.201200434
DO - 10.1002/cmdc.201200434
M3 - Journal article
C2 - 23203920
SN - 1860-7179
VL - 8
SP - 157
EP - 163
JO - Farmaco, Edizione Pratica
JF - Farmaco, Edizione Pratica
IS - 1
ER -
