Computer-aided identification of recognized drugs as Pseudomonas aeruginosa quorum-sensing inhibitors.
Attenuation of Pseudomonas aeruginosa virulence by the use of small-molecule quorum-sensing inhibitors (referred to as the antipathogenic drug principle) is likely to play a role in future treatment strategies for chronic infections. In this study, structure-based virtual screening was used in a search for putative quorum-sensing inhibitors from a database comprising approved drugs and natural compounds. The database was built from compounds which showed structural similarities to previously reported quorum-sensing inhibitors, the ligand of the P. aeruginosa quorum-sensing receptor LasR, and a quorum-sensing receptor agonist. Six top-ranking compounds, all recognized drugs, were identified and tested for quorum-sensing-inhibitory activity. Three compounds, salicylic acid, nifuroxazide, and chlorzoxazone, showed significant inhibition of quorum-sensing-regulated gene expression and related phenotypes in a dose-dependent manner. These results suggest that the identified compounds have the potential to be used as antipathogenic drugs. Furthermore, the results indicate that structure-based virtual screening is an efficient tool in the search for novel compounds to combat bacterial infections.
Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
Liang
L
Yang
Morten Theil
MT
Rybtke
Tim Holm
TH
Jakobsen
Morten
M
Hentzer
Thomas
T
Bjarnsholt
Michael
M
Givskov
Tim
T
Tolker-Nielsen
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D018441:Biofilms / Q000187:drug effects; D002753:Chlorzoxazone / Q000494:pharmacology*; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D062385:Hydroxybenzoates / Q000494:pharmacology*; D009581:Nitrofurans / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D053038:Quorum Sensing / Q000187:drug effects*; D020156:Salicylic Acid / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D037521:Virulence Factors / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D062385:Hydroxybenzoates; C080365:LasR protein, Pseudomonas aeruginosa; D009581:Nitrofurans; D015534:Trans-Activators; D037521:Virulence Factors; D002753:Chlorzoxazone; D020156:Salicylic Acid; C013150:nifuroxazide