ABSTRACTBackgroundPseudomonas aeruginosais 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. aeruginosais an antibiotic-resistant opportunistic human pathogen. It affects patients with AIDS, cystic fibrosis, cancer, burn victims and people with prosthetics and implants.P. aeruginosaalso 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 againstP. 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 inhibitsPseudomonas aeruginosabiofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with quercetin.ResultsWe used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques for the study of the interaction of the LasR protein ofP. aeruginosawith 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.ConclusionsThis 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.List of abbreviationsPDBProtein data bankMDMolecular DynamicsPCAPrincipal Component AnalysisPCPrincipal ComponentSLRShort Linker RegionBLASTBasic local alignment search toolDBIDavid-Bouldin IndexpsFpseudo-F statistic
Conformational transitions induced by γ-amino butyrate binding in GabR, a bacterial transcriptional regulator