Pseudomonas aeruginosa is the common cause of life-threating nosocomial infections that have become increasingly difficult to treat due to biofilm formation. Biofilm formation in P. aeruginosa is majorly associated with the LasR-LasI quorum sensing regulation system. As such, there is an urgent need for the discovery and development of LasR modulators. In this study, the anti-LasR activity of bioactives from essential oils (buchu, wormwood, rose geranium, verbena, and lemongrass) were evaluated using computational techniques. The thermodynamic refinements and stability, feasible synthetic score, and pharmacokinetics properties of the top five essential oil components with the highest negative docking scores against LasR were determined over a 200 ns MD simulation period. The results revealed that the lead compounds had higher binding free energies relative to the two standards [cinnamaldehyde (-16.06 kcal/mol), erythromycin (-30.75 kcal/mol)] and N-3-oxo-dodecanoyl-homoserinelactone native ligand (-25.26 kcal/mol), with geranyl linalool (-53.41 kcal/mol) having the highest score. The top five lead molecules complexed with LasR showed thermodynamic stability, with geranyl tiglate (1.45 Å) exhibiting the best stability. The lead compounds quantum features assessed using DFT/B3LYP revealed that geranyl linalool had the highest ionization energy and electron affinity, suggesting its better potential to interact with LasR active site relative to other investigated compounds. While these observations lent credence to geranyl linalool as the most promising LasR modulator, further confirmatory efforts via in vitro and in vivo studies are ongoing.
Keywords: Quorum sensing, Pseudomonas aeruginosa, LasR, Essential oils, Molecular dynamics simulation