Targeting Quorum Sensing in Pseudomonas aeruginosa Using Marine‐Derived Metabolites—An In Silico Approach

Abstract

Quorum sensing (QS), a cell‐to‐cell communication among bacteria, is one of the leading mechanisms of antibiotic resistance. Opportunistic bacteria such as Pseudomonas aeruginosa employ QS in their pathogenicity. Marine‐derived natural products have been reported to elicit good antimicrobial and anti‐QS properties. In this work, 30 marine‐derived metabolites were screened against the LasR, PqsR, and RhlR QS receptors of P. aeruginosa using molecular docking and dynamics simulation approach. From virtual screening, 11, 9, and 7 compounds had a preferential affinity for the LasR, PqsR, and RhlR receptors, respectively. For LasR, docking scores between −10.2 and −5.1 kcal/mol were obtained for the compounds. Binding scores of −7.3 to −5.6 kcal/mol and −9.1 to −7.1 kcal/mol were also obtained for PqsR and RhlR, respectively. Interaction with Gln 194, Tyr 258, Ile 236, Leu 208, and Leu 207 catalytic residues were observed for PqsR complexes. Molecular dynamics (MD) simulations revealed that all 11 compounds retained their docking poses with LasR, while 6 compounds maintained stable interactions with PqsR and RhlR. MD show that compounds bind to LasR and RhlR by causing high conformational changes in their DNA‐binding domains (DBDs), as demonstrated by a principal component analysis (PCA) of the respective DBDs. In PqsR, the compounds interacted with crucial residues (Gln 194, Tyr 258, Ile 236, Leu 236, and Leu 207) previously reported as residues necessary for the inhibition of PqsR and maintained these interactions during the simulation. Thus, the compounds exhibited their quorum quenching activity by attenuating DNA recognition in LasR and RhlR while competitively targeting the PqsR binding site. The high binding affinities observed suggest that these marine‐derived compounds could effectively inhibit QS in P. aeruginosa, offering a promising strategy for addressing biofilm‐related infections and antibiotic resistance.