In silico Identification of Potential Quorum-Sensing Inhibitors Against the AgrA of Staphylococcus aureus
Abstract
AgrA (Accessory gene regulator) plays a crucial role as a regulator in the agr quorum-sensing system by controlling the production of virulence factors, including exotoxins and enzymes involved in the pathogenesis of Staphylococcus aureus. The emergence of resistant strains highlights the urgent need for alternative therapeutic agents. Therefore, in this study, molecular docking of potential phytochemicals was performed against AgrA, followed by the evaluation of pharmacokinetic properties, allergenicity, and toxicity. Binding free energies were predicted using AutoDock Vina 1.5.6. Diosgenin, stigmasterol, hypericin, and betulin exhibited strong binding interactions with critical residues of AgrA, while colchicine, procyanidin B2, and quinine interacted with the transcriptional activation site of AgrA with high binding affinities, forming significant hydrogen bond interactions. The non-toxic, non-allergenic, and favorable pharmacokinetic properties of these compounds suggest that these phytochemicals could be developed into drugs for use in combination with antibiotics as adjuvants or synergists, pending further in vitro and in vivo evaluation.
Keywords:
Agra Gene, Plant-Derived Compounds, Quorum-Sensing Inhibitors, Staphylococcus Aureus
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References
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Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 42717. https://doi.org/10.1038/srep42717
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Gajdács, M., & Spengler, G. (2019). The role of drug repurposing in the development of novel antimicrobial drugs: Non-antibiotic pharmacological agents as quorum sensing-inhibitors. Antibiotics, 8(4), 270. https://doi.org/10.3390/antibiotics8040270
Gordon, C. P., Williams, P., & Chan, W. C. (2013). Attenuating Staphylococcus aureus virulence gene regulation: a medicinal chemistry perspective. Journal of Medicinal Chemistry, 56(4), 1389-1404. https://doi.org/10.1021/jm3014635
Heyer, G., Saba, S., Adamo, R., Rush, W., Soong, G., Cheung, A., & Prince, A. (2002). Staphylococcus aureus agr and sarA functions are required for invasive infection but not inflammatory responses in the lung. Infection and Immunity, 70(1), 127-133. https://doi.org/10.1128/iai.70.1.127-133.2002
Kar, A., Mukherjee, S. K., & Hossain, S. T. (2025). Quorum sensing mediated attenuation of biofilm formation and virulence traits in Staphylococcus aureus by trigonelline. Microbial Pathogenesis, 205, 107731. https://doi.org/10.1016/j.micpath.2025.107731
Li, X., He, C., Song, L., Li, T., Cui, S., Zhang, L., & Jia, Y. (2017). Antimicrobial activity and mechanism of Larch bark procyanidins against Staphylococcus aureus. Acta Biochimica et Biophysica Sinica, 49(12), 1058-1066. https://doi.org/10.1093/abbs/gmx112
Manu, P., Nketia, P. B., Osei-Poku, P., & Kwarteng, A. (2024). Computational mutagenesis and inhibition of Staphylococcus aureus AgrA LytTR domain using phenazine scaffolds: Insight from a biophysical study. BioMed Research International, 2024(1), 8843954. https://doi.org/10.1155/2024/8843954
Murray, E. J., Crowley, R. C., Truman, A., Clarke, S. R., Cottam, J. A., Jadhav, G. P., ... & Williams, P. (2014). Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors. Journal of Medicinal Chemistry, 57(6), 2813-2819. https://doi.org/10.1021/jm500215s
Nicod, S. S., Weinzierl, R. O., Burchell, L., Escalera-Maurer, A., James, E. H., & Wigneshweraraj, S. (2014). Systematic mutational analysis of the LytTR DNA binding domain of Staphylococcus aureus virulence gene transcription factor AgrA. Nucleic Acids Research, 42(20), 12523-12536. https://doi.org/10.1093/nar/gku1015
Otto, M. (2023). Critical assessment of the prospects of quorum-quenching therapy for Staphylococcus aureus infection. International Journal of Molecular Sciences, 24(4), 4025. https://doi.org/10.3390/ijms24044025
Patel, H., & Rawat, S. (2023). A genetic regulatory see-saw of biofilm and virulence in MRSA pathogenesis. Frontiers in Microbiology, 14, 1204428. https://doi.org/10.3389/fmicb.2023.1204428
Qader, T. A., Ali, M. R., & Alsakini, A. H. (2025). Genotyping and siRNA-Mediated quorum sensing inhibition in Staphylococcus aureus: Exploring new approaches for treating persistent infections. Journal of Bioscience and Applied Research, 11(1), 196-213. https://doi.org/10.21608/jbaar.2025.419043
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Ramasamy, M., Vetrivel, A., Venugopal, S., & Murugesan, R. (2023). Identification of inhibitors for Agr quorum sensing system of Staphylococcus aureus by machine learning, pharmacophore modeling, and molecular dynamics approaches. Journal of Molecular Modeling, 29(8), 258. https://doi.org/10.1007/s00894-023-05647-9
Sharma, N., Patiyal, S., Dhall, A., Devi, N. L., & Raghava, G. P. (2021). ChAlPred: a web server for prediction of allergenicity of chemical compounds. Computers in Biology and Medicine, 136, 104746. https://doi.org/10.1016/j.compbiomed.2021.104746
Sully, E. K., Malachowa, N., Elmore, B. O., Alexander, S. M., Femling, J. K., Gray, B. M., ... & Gresham, H. D. (2014). Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathogens, 10(6), e1004174. https://doi.org/10.1371/journal.ppat.1004174
Tong, S. Y., Davis, J. S., Eichenberger, E., Holland, T. L., & Fowler Jr, V. G. (2015). Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clinical Microbiology Reviews, 28(3), 603-661. https://doi.org/10.1128/cmr.00134-14
Touati, A., Ibrahim, N. A., & Idres, T. (2025). Disarming Staphylococcus aureus: Review of Strategies Combating This Resilient Pathogen by Targeting Its Virulence. Pathogens, 14(4), 386. https://doi.org/10.3390/pathogens14040386
Turner, N. A., Sharma-Kuinkel, B. K., Maskarinec, S. A., Eichenberger, E. M., Shah, P. P., Carugati, M., ... & Fowler Jr, V. G. (2019). Methicillin-resistant Staphylococcus aureus: An overview of basic and clinical research. Nature Reviews Microbiology, 17(4), 203-218. https://doi.org/10.1038/s41579-018-0147-4
Vivek-Ananth, R. P., Rana, A., Rajan, N., Biswal, H. S., & Samal, A. (2020). In silico identification of potential natural product inhibitors of human proteases key to SARS-CoV-2 infection. Molecules, 25(17), 3822. https://doi.org/10.3390/molecules25173822
Wardenburg, J. B., Patel, R. J., & Schneewind, O. (2007). Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infection and Immunity, 75(2), 1040-1044. https://doi.org/10.1128/iai.01313-06
Wright III, J. S., Jin, R., & Novick, R. P. (2005). Transient interference with staphylococcal quorum sensing blocks abscess formation. Proceedings of the National Academy of Sciences, 102(5), 1691-1696. https://doi.org/10.1073/pnas.0407661102
Xia, S., Ma, L., Wang, G., Yang, J., Zhang, M., Wang, X., ... & Xie, M. (2022). In vitro antimicrobial activity and the mechanism of berberine against methicillin-resistant Staphylococcus aureus isolated from bloodstream infection patients. Infection and Drug Resistance, 15, 1933-1944. https://doi.org/10.2147/IDR.S357077
Yamaguchi, J., Manome, T., Hara, Y., Yamazaki, Y., Nakamura, Y., Ishibashi, M., & Takaya, A. (2024). Physalin H, physalin B, and isophysalin B suppress the quorum-sensing function of Staphylococcus aureus by binding to AgrA. Frontiers in Pharmacology, 15, 1365815. https://doi.org/10.3389/fphar.2024.1365815
Zhou, K., Shi, M., Chen, R., Zhang, Y., Sheng, Y., Tong, C., ... & Shou, D. (2025). Natural phytochemical-based strategies for antibiofilm applications. Chinese Medicine, 20(1), 96. https://doi.org/10.1186/s13020-025-01147-5
Banerjee, P., Kemmler, E., Dunkel, M., & Preissner, R. (2024). ProTox 3.0: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Research, 52(W1), W513-W520. https://doi.org/10.1093/nar/gkae303
Baysal, N. B., Emecen, A. N., Arslan, F., & Vahaboğlu, H. (2019). Metisilin Dirençli Staphylococcus aureus Septik Artriti Olgu Sunumu: Kolşisinin Olası Etkisi [Case Report of Methicillin-Resistant Staphylococcus aureus Septic Arthritis: Possible Effects of Colchicine]. Mediterranean Journal of Infection Microbes and Antimicrobials, 8(1), 12. https://doi.org/10.4274/mjima.galenos.2019.2019.12
Booth, M. C., Atkuri, R. V., Nanda, S. K., Iandolo, J. J., & Gilmore, M. S. (1995). Accessory gene regulator controls Staphylococcus aureus virulence in endophthalmitis. Investigative Ophthalmology & Visual Science, 36(9), 1828-1836. https://iovs.arvojournals.org/article.aspx?articleid=2180197
Bronner, S., Monteil, H., & Prévost, G. (2004). Regulation of virulence determinants in Staphylococcus aureus: complexity and applications. FEMS Microbiology Reviews, 28(2), 183-200. https://doi.org/10.1016/j.femsre.2003.09.003
Cui, S., & Kim, E. (2024). Quorum sensing and antibiotic resistance in polymicrobial infections. Communicative & Integrative Biology, 17(1), 2415598. https://doi.org/10.1080/19420889.2024.2415598
Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 42717. https://doi.org/10.1038/srep42717
Das, S., Dasgupta, A., & Chopra, S. (2016). Drug repurposing: a new front in the war against Staphylococcus aureus. Future Microbiology, 11(8), 1091-1099. https://doi.org/10.2217/fmb-2016-0021
Gajdács, M., & Spengler, G. (2019). The role of drug repurposing in the development of novel antimicrobial drugs: Non-antibiotic pharmacological agents as quorum sensing-inhibitors. Antibiotics, 8(4), 270. https://doi.org/10.3390/antibiotics8040270
Gordon, C. P., Williams, P., & Chan, W. C. (2013). Attenuating Staphylococcus aureus virulence gene regulation: a medicinal chemistry perspective. Journal of Medicinal Chemistry, 56(4), 1389-1404. https://doi.org/10.1021/jm3014635
Heyer, G., Saba, S., Adamo, R., Rush, W., Soong, G., Cheung, A., & Prince, A. (2002). Staphylococcus aureus agr and sarA functions are required for invasive infection but not inflammatory responses in the lung. Infection and Immunity, 70(1), 127-133. https://doi.org/10.1128/iai.70.1.127-133.2002
Kar, A., Mukherjee, S. K., & Hossain, S. T. (2025). Quorum sensing mediated attenuation of biofilm formation and virulence traits in Staphylococcus aureus by trigonelline. Microbial Pathogenesis, 205, 107731. https://doi.org/10.1016/j.micpath.2025.107731
Li, X., He, C., Song, L., Li, T., Cui, S., Zhang, L., & Jia, Y. (2017). Antimicrobial activity and mechanism of Larch bark procyanidins against Staphylococcus aureus. Acta Biochimica et Biophysica Sinica, 49(12), 1058-1066. https://doi.org/10.1093/abbs/gmx112
Manu, P., Nketia, P. B., Osei-Poku, P., & Kwarteng, A. (2024). Computational mutagenesis and inhibition of Staphylococcus aureus AgrA LytTR domain using phenazine scaffolds: Insight from a biophysical study. BioMed Research International, 2024(1), 8843954. https://doi.org/10.1155/2024/8843954
Murray, E. J., Crowley, R. C., Truman, A., Clarke, S. R., Cottam, J. A., Jadhav, G. P., ... & Williams, P. (2014). Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors. Journal of Medicinal Chemistry, 57(6), 2813-2819. https://doi.org/10.1021/jm500215s
Nicod, S. S., Weinzierl, R. O., Burchell, L., Escalera-Maurer, A., James, E. H., & Wigneshweraraj, S. (2014). Systematic mutational analysis of the LytTR DNA binding domain of Staphylococcus aureus virulence gene transcription factor AgrA. Nucleic Acids Research, 42(20), 12523-12536. https://doi.org/10.1093/nar/gku1015
Otto, M. (2023). Critical assessment of the prospects of quorum-quenching therapy for Staphylococcus aureus infection. International Journal of Molecular Sciences, 24(4), 4025. https://doi.org/10.3390/ijms24044025
Patel, H., & Rawat, S. (2023). A genetic regulatory see-saw of biofilm and virulence in MRSA pathogenesis. Frontiers in Microbiology, 14, 1204428. https://doi.org/10.3389/fmicb.2023.1204428
Qader, T. A., Ali, M. R., & Alsakini, A. H. (2025). Genotyping and siRNA-Mediated quorum sensing inhibition in Staphylococcus aureus: Exploring new approaches for treating persistent infections. Journal of Bioscience and Applied Research, 11(1), 196-213. https://doi.org/10.21608/jbaar.2025.419043
Queck, S. Y., Jameson-Lee, M., Villaruz, A. E., Bach, T. H. L., Khan, B. A., Sturdevant, D. E., ... & Otto, M. (2008). RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Molecular Cell, 32(1), 150-158. https://doi.org/doi:10.1016/j.molcel.2008.08.005
Ramasamy, M., Vetrivel, A., Venugopal, S., & Murugesan, R. (2023). Identification of inhibitors for Agr quorum sensing system of Staphylococcus aureus by machine learning, pharmacophore modeling, and molecular dynamics approaches. Journal of Molecular Modeling, 29(8), 258. https://doi.org/10.1007/s00894-023-05647-9
Sharma, N., Patiyal, S., Dhall, A., Devi, N. L., & Raghava, G. P. (2021). ChAlPred: a web server for prediction of allergenicity of chemical compounds. Computers in Biology and Medicine, 136, 104746. https://doi.org/10.1016/j.compbiomed.2021.104746
Sully, E. K., Malachowa, N., Elmore, B. O., Alexander, S. M., Femling, J. K., Gray, B. M., ... & Gresham, H. D. (2014). Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathogens, 10(6), e1004174. https://doi.org/10.1371/journal.ppat.1004174
Tong, S. Y., Davis, J. S., Eichenberger, E., Holland, T. L., & Fowler Jr, V. G. (2015). Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clinical Microbiology Reviews, 28(3), 603-661. https://doi.org/10.1128/cmr.00134-14
Touati, A., Ibrahim, N. A., & Idres, T. (2025). Disarming Staphylococcus aureus: Review of Strategies Combating This Resilient Pathogen by Targeting Its Virulence. Pathogens, 14(4), 386. https://doi.org/10.3390/pathogens14040386
Turner, N. A., Sharma-Kuinkel, B. K., Maskarinec, S. A., Eichenberger, E. M., Shah, P. P., Carugati, M., ... & Fowler Jr, V. G. (2019). Methicillin-resistant Staphylococcus aureus: An overview of basic and clinical research. Nature Reviews Microbiology, 17(4), 203-218. https://doi.org/10.1038/s41579-018-0147-4
Vivek-Ananth, R. P., Rana, A., Rajan, N., Biswal, H. S., & Samal, A. (2020). In silico identification of potential natural product inhibitors of human proteases key to SARS-CoV-2 infection. Molecules, 25(17), 3822. https://doi.org/10.3390/molecules25173822
Wardenburg, J. B., Patel, R. J., & Schneewind, O. (2007). Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infection and Immunity, 75(2), 1040-1044. https://doi.org/10.1128/iai.01313-06
Wright III, J. S., Jin, R., & Novick, R. P. (2005). Transient interference with staphylococcal quorum sensing blocks abscess formation. Proceedings of the National Academy of Sciences, 102(5), 1691-1696. https://doi.org/10.1073/pnas.0407661102
Xia, S., Ma, L., Wang, G., Yang, J., Zhang, M., Wang, X., ... & Xie, M. (2022). In vitro antimicrobial activity and the mechanism of berberine against methicillin-resistant Staphylococcus aureus isolated from bloodstream infection patients. Infection and Drug Resistance, 15, 1933-1944. https://doi.org/10.2147/IDR.S357077
Yamaguchi, J., Manome, T., Hara, Y., Yamazaki, Y., Nakamura, Y., Ishibashi, M., & Takaya, A. (2024). Physalin H, physalin B, and isophysalin B suppress the quorum-sensing function of Staphylococcus aureus by binding to AgrA. Frontiers in Pharmacology, 15, 1365815. https://doi.org/10.3389/fphar.2024.1365815
Zhou, K., Shi, M., Chen, R., Zhang, Y., Sheng, Y., Tong, C., ... & Shou, D. (2025). Natural phytochemical-based strategies for antibiofilm applications. Chinese Medicine, 20(1), 96. https://doi.org/10.1186/s13020-025-01147-5
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Sowmiya, A., Purushothaman, I., Selvam, K., & Sangeetha, K. (2026). In silico Identification of Potential Quorum-Sensing Inhibitors Against the AgrA of Staphylococcus aureus. International Journal of Advancement in Life Sciences Research, 9(1), 82-95. https://doi.org/https://doi.org/10.31632/ijalsr.2026.v09i01.006
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