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

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Abstract

Pseudomonas aeruginosa is an opportunistic pathogen, having complicated quorum sensing (QS) system utilizing multiple signals and receptors to coordinate virulence and pathogenicity. N-acyl-homoserine-lactones (AHLs) are the most common autoinducers responsible for regulation of QS-mediated virulence gene expression. There are four QS systems in P. aeruginosa among which the LasI/R and RhlI/R systems are regulated by 3-oxo-C12-HSL and C4-HSL respectively. They play a major role in host-associated pathogenesis. The LasR and RhlR binding specificity to cognate or non-cognate HSLs influences the QS-mediated responses. Here, we used computational approaches to consolidate the interaction of different types of HSLs produced by P. aeruginosa with LasR and RhlR receptors. To explore the binding affinity, fourteen different AHLs were subjected for molecular docking analysis with LasR and RhlR receptors. The RhlR was modelled using MMseqs2 in ColabFold: Alpha fold 2. Further, to validate the stability and interaction mechanism, molecular dynamic simulations was performed with the top docked six HSLs for 100 ns. In docking results, apart from 3-oxo-C12-HSL and C4-HSL, other HSLs such as C16-HSL and C6-HSL showed better binding affinity towards LasR and RhlR proteins, respectively. Further validation by molecular dynamic simulations showed that 3-oxo-C10-HSL and 3-oxo-C6-HSL formed stable complex with LasR and RhlR, respectively. Our comprehensive in silico study results may provide promising targets for development of anti-QS drugs against Las/Rhl QS systems.

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Acknowledgements

We thank PSGCP for Schrodinger support.

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  1. Devasahayam Arokia Balaya Rex and Kanekar Saptami have contributed equally to this work.

Authors and Affiliations

  1. Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, India

    Devasahayam Arokia Balaya Rex, Kanekar Saptami & Punchappady Devasya Rekha

  2. School of Pharmacy Technology Management, SVKM‘S NMIMS, Telangana, Hyderabad, India

    Jaikanth Chandrasekaran

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Contributions

Punchappady Devasya Rekha, Jaikanth Chandrasekaran and Devasahayam Arokia Balaya Rex have equally contributed in designing and executing the study. Jaikanth Chandrasekaran, Devasahayam Arokia Balaya Rex and Kanekar Saptami analysed the results and prepared the manuscript. Jaikanth Chandrasekaran and Devasahayam Arokia Balaya Rex performed the in silico studies, homology modelling and data analysis and interpretation. Jaikanth Chandrasekaran and Punchappady Devasya Rekha framed the study, prepared and evaluated the manuscript. All the authors have read and approved the manuscript for submission.

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Correspondence to Jaikanth Chandrasekaran or Punchappady Devasya Rekha.

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Rex, D.A.B., Saptami, K., Chandrasekaran, J. et al. Pleotropic potential of quorum sensing mediated N-acyl homoserine lactones (AHLs) at the LasR and RhlR receptors of Pseudomonas aeruginosa. Struct Chem 34, 1327–1339 (2023). https://doi.org/10.1007/s11224-022-02115-7

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