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Interaction of quercetin with transcriptional regulator LasR of Pseudomonas aeruginosa: Mechanistic insights of the inhibition of virulence through quorum sensing

View ORCID ProfileHovakim Grabski, Lernik Hunanyan, Susanna Tiratsuyan, Hrachik Vardapetyan
doi: https://doi.org/10.1101/239996
Hovakim Grabski
1Department of Medical Biochemistry and Biotechnology, Bioinformatics Group, Russian-Armenian University, Yerevan, Armenia
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  • ORCID record for Hovakim Grabski
  • For correspondence: hovakim.grabski@rau.am
Lernik Hunanyan
1Department of Medical Biochemistry and Biotechnology, Bioinformatics Group, Russian-Armenian University, Yerevan, Armenia
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Susanna Tiratsuyan
1Department of Medical Biochemistry and Biotechnology, Bioinformatics Group, Russian-Armenian University, Yerevan, Armenia
2Faculty of Biology, Yerevan State University, Yerevan, Armenia
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Hrachik Vardapetyan
1Department of Medical Biochemistry and Biotechnology, Bioinformatics Group, Russian-Armenian University, Yerevan, Armenia
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ABSTRACT

Background Pseudomonas aeruginosa is one of the most dangerous superbugs in the list of bacteria for which new antibiotics are urgently needed, which was published by World Health Organization. P. aeruginosa is an antibiotic-resistant opportunistic human pathogen. It affects patients with AIDS, cystic fibrosis, cancer, burn victims and people with prosthetics and implants. P. aeruginosa also forms biofilms. Biofilms increase resistance to antibiotics and host immune responses. Because of biofilms, current therapies are not effective. It is important to find new antibacterial treatment strategies against P. aeruginosa. Biofilm formation is regulated through a system called quorum sensing. Thus disrupting this system is considered a promising strategy to combat bacterial pathogenicity. It is known that quercetin inhibits Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with quercetin.

Results We used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques for the study of the interaction of the LasR protein of P. aeruginosa with quercetin. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of quercetin with LasR. We show that quercetin has two binding modes. One binding mode is the interaction with ligand binding domain, this interaction is not competitive and it has also been shown experimentally. The second binding mode is the interaction with the bridge, it involves conservative amino acid interactions from LBD, SLR, and DBD and it is also not competitive. Experimental studies show hydroxyl group of ring A is necessary for inhibitory activity, in our model the hydroxyl group interacts with Leu177 during the second binding mode. This could explain the molecular mechanism of how quercetin inhibits LasR protein.

Conclusions This study may offer insights on how quercetin inhibits quorum sensing circuitry by interacting with transcriptional regulator LasR. The capability of having two binding modes may explain why quercetin is effective at inhibiting biofilm formation and virulence gene expression.

PDB
Protein data bank
MD
Molecular Dynamics
PCA
Principal Component Analysis
PC
Principal Component
SLR
Short Linker Region
BLAST
Basic local alignment search tool
DBI
David-Bouldin Index
psF
pseudo-F statistic

Footnotes

  • E-mail addresses: hovakim.grabski{at}rau.am, lernik.hunanyan{at}rau.am, susanna.tiratsuyan{at}rau.am, hrachik.vardapetyan{at}rau.am

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 27, 2017.
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Interaction of quercetin with transcriptional regulator LasR of Pseudomonas aeruginosa: Mechanistic insights of the inhibition of virulence through quorum sensing
Hovakim Grabski, Lernik Hunanyan, Susanna Tiratsuyan, Hrachik Vardapetyan
bioRxiv 239996; doi: https://doi.org/10.1101/239996
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Interaction of quercetin with transcriptional regulator LasR of Pseudomonas aeruginosa: Mechanistic insights of the inhibition of virulence through quorum sensing
Hovakim Grabski, Lernik Hunanyan, Susanna Tiratsuyan, Hrachik Vardapetyan
bioRxiv 239996; doi: https://doi.org/10.1101/239996

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