Pleotropic potential of quorum sensing mediated N-acyl homoserine lactones (AHLs) at the LasR and RhlR receptors of Pseudomonas aeruginosa

Rex, Devasahayam Arokia Balaya; Kanekar, Saptami; Chandrasekaran, Jaikanth; Rekha, P. D.

doi:10.1007/s11224-022-02115-7

Cited by 2 publications

(1 citation statement)

References 36 publications

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“…In P. aeruginosa , the LasR protein is a key component that acts as a transcription factor that regulates the expression of numerous genes involved in virulence factors production, biofilm formation, and other important physiological processes ( Liu et al, 2009 ). LasR is a receptor protein that binds to small signaling molecules called N-acyl homoserine lactones ( Rex et al, 2022 ). When the concentration of these molecules reaches a certain threshold, LasR undergoes a conformational change, enabling it to bind to specific DNA sequences and activate the expression of target genes ( Kiratisin, Tucker & LJJob, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

In silico and in vitro evaluation of the anti-virulence potential of patuletin, a natural methoxy flavone, against Pseudomonas aeruginosa

Metwaly,

Saleh,

Alsfouk

et al. 2024

PeerJ

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This study aimed to investigate the potential of patuletin, a rare natural flavonoid, as a virulence and LasR inhibitor against Pseudomonas aeruginosa. Various computational studies were utilized to explore the binding of Patuletin and LasR at a molecular level. Molecular docking revealed that Patuletin strongly interacted with the active pocket of LasR, with a high binding affinity value of −20.96 kcal/mol. Further molecular dynamics simulations, molecular mechanics generalized Born surface area (MM/GBSA), protein-ligand interaction profile (PLIP), and essential dynamics analyses confirmed the stability of the patuletin-LasR complex, and no significant structural changes were observed in the LasR protein upon binding. Key amino acids involved in binding were identified, along with a free energy value of −26.9 kcal/mol. In vitro assays were performed to assess patuletin’s effects on P. aeruginosa. At a sub-inhibitory concentration (1/4 MIC), patuletin significantly reduced biofilm formation by 48% and 42%, decreased pyocyanin production by 24% and 14%, and decreased proteolytic activities by 42% and 20% in P. aeruginosa isolate ATCC 27853 (PA27853) and P. aeruginosa clinical isolate (PA1), respectively. In summary, this study demonstrated that patuletin effectively inhibited LasR activity in silico and attenuated virulence factors in vitro, including biofilm formation, pyocyanin production, and proteolytic activity. These findings suggest that patuletin holds promise as a potential therapeutic agent in combination with antibiotics to combat antibiotic-tolerant P. aeruginosa infections.

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Section: Introductionmentioning

confidence: 99%

In silico and in vitro evaluation of the anti-virulence potential of patuletin, a natural methoxy flavone, against Pseudomonas aeruginosa

Metwaly,

Saleh,

Alsfouk

et al. 2024

PeerJ

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

Padiga Seidu,

Adomako,

Boakye

et al. 2024

Journal of Chemistry

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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.

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Pleotropic potential of quorum sensing mediated N-acyl homoserine lactones (AHLs) at the LasR and RhlR receptors of Pseudomonas aeruginosa

Cited by 2 publications

References 36 publications

In silico and in vitro evaluation of the anti-virulence potential of patuletin, a natural methoxy flavone, against Pseudomonas aeruginosa

In silico and in vitro evaluation of the anti-virulence potential of patuletin, a natural methoxy flavone, against Pseudomonas aeruginosa

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

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