Computational discovery of putative quorum sensing inhibitors against LasR and RhlR receptor proteins of Pseudomonas aeruginosa

Drugs have been discovered in the past mainly either by identification of active components from traditional remedies or by unpredicted discovery. A key motivation for the study of structure based virtual screening is the exploitation of such information to design targeted drugs. In this study, structure based virtual screening was used in search for putative quorum sensing inhibitors (QSI) of Pseudomonas aeruginosa. The virtual screening programme Glide version 5.5 was applied to screen 1,920 natural compounds/drugs against LasR and RhlR receptor proteins of P. aeruginosa. Based on the results of in silico docking analysis, five top ranking compounds namely rosmarinic acid, naringin, chlorogenic acid, morin and mangiferin were subjected to in vitro bioassays against laboratory strain PAO1 and two more antibiotic resistant clinical isolates, P. aeruginosa AS1 (GU447237) and P. aeruginosa AS2 (GU447238). Among the five compounds studied, except mangiferin other four compounds showed significant inhibition in the production of protease, elastase and hemolysin. Further, all the five compounds potentially inhibited the biofilm related behaviours. This interaction study provided promising ligands to inhibit the quorum sensing (QS) mediated virulence factors production in P. aeruginosa.

[1]  Roger S Smith,et al.  Pseudomonas aeruginosa quorum sensing as a potential antimicrobial target. , 2003, The Journal of clinical investigation.

[2]  S. Kjelleberg,et al.  Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors , 2003, The EMBO journal.

[3]  K. Mathee,et al.  Inhibition of Quorum Sensing-Controlled Virulence Factor Production in Pseudomonas aeruginosa by South Florida Plant Extracts , 2007, Antimicrobial Agents and Chemotherapy.

[4]  O. Ciofu,et al.  Development of antibiotic resistance in Pseudomonas aeruginosa during two decades of antipseudomonal treatment at the Danish CF Center , 1994, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[5]  J. Costerton.  Cystic fibrosis pathogenesis and the role of biofilms in persistent infection. , 2001, Trends in microbiology.

[6]  S. Molin,et al.  Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent. , 2005, Microbiology.

[7]  R. McLean,et al.  Dietary phytochemicals as quorum sensing inhibitors. , 2007, Fitoterapia.

[8]  S. Cryz,et al.  Isolation andCharacterization ofaPseudomonas aeruginosa PAOMutantThatProduces Altered Elastase , 1980 .

[9]  V. Saroja,et al.  Antipathogenic potential of marine Bacillus sp. SS4 on N-acyl-homoserine-lactone-mediated virulence factors production in Pseudomonas aeruginosa (PAO1) , 2011, Journal of Biosciences.

[10]  T. B. Rasmussen,et al.  Quorum sensing inhibitors: a bargain of effects. , 2006, Microbiology.

[11]  C. Passariello,et al.  Proteolytic enzymes: a new treatment strategy for prosthetic infections? , 1993, Antimicrobial Agents and Chemotherapy.

[12]  B. Iglewski,et al.  Cell-to-cell signaling and Pseudomonas aeruginosa infections. , 1998, Emerging infectious diseases.

[13]  A. Griffin,et al.  Evolutionary theory of bacterial quorum sensing: when is a signal not a signal? , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[14]  J. Irwin,et al.  Docking and chemoinformatic screens for new ligands and targets. , 2009, Current opinion in biotechnology.

[15]  Lixiang Cao,et al.  Virtual screening for novel quorum sensing inhibitors to eradicate biofilm formation of Pseudomonas aeruginosa , 2008, Applied Microbiology and Biotechnology.

[16]  M. Givskov,et al.  Quorum sensing inhibition: targeting chemical communication in gram-negative bacteria. , 2005, Current medicinal chemistry.

[17]  S. Diggle,et al.  The Pseudomonas aeruginosa quinolone signal molecule overcomes the cell density‐dependency of the quorum sensing hierarchy, regulates rhl‐dependent genes at the onset of stationary phase and can be produced in the absence of LasR , 2003, Molecular microbiology.

[18]  Gisbert Schneider,et al.  Virtual screening and fast automated docking methods. , 2002, Drug discovery today.

[19]  J. Costerton,et al.  Testing the susceptibility of bacteria in biofilms to antibacterial agents , 1990, Antimicrobial Agents and Chemotherapy.

[20]  Kristina M Smith,et al.  Molecular mechanisms of bacterial quorum sensing as a new drug target. , 2003, Current opinion in chemical biology.

[21]  S. K. Pandian,et al.  Inhibition of Quorum Sensing Mediated Virulence Factors Production in Urinary Pathogen Serratia marcescens PS1 by Marine Sponges , 2012, Indian Journal of Microbiology.

[22]  Y. Carmeli,et al.  Health and economic outcomes of antibiotic resistance in Pseudomonas aeruginosa. , 1999, Archives of internal medicine.

[23]  Paul D Lyne,et al.  Structure-based virtual screening: an overview. , 2002, Drug discovery today.

[24]  E. Greenberg,et al.  Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  E. Kessler,et al.  In Vitro Inhibition of Pseudomonas aeruginosa Elastase by Metal-Chelating Peptide Derivatives , 1982, Infection and immunity.

[26]  S. K. Pandian,et al.  Methods to determine antipathogenic potential of phenolic and flavonoid compounds against urinary pathogen Serratia marcescens. , 2012, Journal of microbiological methods.

[27]  Hiroaki Suga,et al.  Library screening for synthetic agonists and antagonists of a Pseudomonas aeruginosa autoinducer. , 2003, Chemistry & biology.

[28]  T. B. Rasmussen,et al.  Quorum-sensing inhibitors as anti-pathogenic drugs. , 2006, International journal of medical microbiology : IJMM.

[29]  K. Harjai,et al.  Garlic blocks quorum sensing and attenuates the virulence of Pseudomonas aeruginosa. , 2010, FEMS immunology and medical microbiology.

[30]  R. Bazzo,et al.  Molecular Insights into Quorum Sensing in the Human Pathogen Pseudomonas aeruginosa from the Structure of the Virulence Regulator LasR Bound to Its Autoinducer* , 2007, Journal of Biological Chemistry.

[31]  S. K. Pandian,et al.  Evaluation of Anti-Quorum-Sensing Activity of Edible Plants and Fruits through Inhibition of the N-Acyl-Homoserine Lactone System in Chromobacterium violaceum and Pseudomonas aeruginosa , 2010, Chemotherapy.

[32]  Leo Eberl,et al.  Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. , 2002, Microbiology.

[33]  G. Boşgelmez-Tinaz,et al.  Quorum Sensing in Gram-Negative Bacteria , 2003 .

[34]  Chandrabose Selvaraj,et al.  In silico screening of indinavir-based compounds targeting proteolytic activity in HIV PR: binding pocket fit approach , 2011, Medicinal Chemistry Research.

[35]  T. Tolker-Nielsen,et al.  Computer-Aided Identification of Recognized Drugs as Pseudomonas aeruginosa Quorum-Sensing Inhibitors , 2009, Antimicrobial Agents and Chemotherapy.

[36]  S. Ulusoy,et al.  Characterization of N-butanoyl-L-homoserine lactone (C4-HSL) deficient clinical isolates of Pseudomonas aeruginosa. , 2008, Microbial pathogenesis.