Skip to main content
SpringerLink
Log in

The inhibitory mechanism of echinacoside against Staphylococcus aureus Ser/Thr phosphatase Stp1 by virtual screening and molecular modeling

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

  • 1 Altmetric

Abstract

Context

Stp1 is a new potential target closely related to the pathogenicity of Staphylococcus aureus (S. aureus). In this study, effective Stp1 inhibitors were screened via virtual screening and enzyme activity experiments, and the inhibition mechanism was analyzed using molecular dynamics simulation.

Methods

AutoDock Vina 4.0 software was used for virtual screening. The molecular structures of Stp1 and ligands were obtained from the RCSB Protein Data Bank and Zinc database, respectively. The molecular dynamics simulation used the Gromacs 4.5.5 software package with the Amberff99sb force field and TIP3P water model. AutoDock Tools was used to add polar hydrogen atoms to Stp1 and distribute part of the charge generated by Kollman’s combined atoms. The binding free energies were calculated using the Amber 10 package.

Results

The theoretical calculation results are consistent with the experimental results. We found that echinacoside (ECH) substantially inhibits the hydrolytic activity of Stp1. ECH competes with the substrate by binding to the active center of Stp1, resulting in a decrease in Stp1 activity. In addition, Met39, Gly41, Asp120, Asn162, and Ile163 were identified to play key roles in the binding of Stp1 to ECH. The benzene ring of ECH also plays an important role in complex binding. These findings provide a robust foundation for the development of innovative anti-infection drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Ronco T, Stegger M, Pedersen K (2017) Draft genome sequence of a sequence type 398 methicillin-resistant Staphylococcus aureus isolate from a Danish dairy cow with mastitis. Microbiol Resour Announc 5:1–2. https://doi.org/10.1128/genomeA.00492-17

    Article  Google Scholar 

  2. Cuny C, Witte W (2017) MRSA in equine hospitals and its significance for infections in humans. Vet Microbiol 200:59–64. https://doi.org/10.1016/j.vetmic.2016.01.013

    Article  PubMed  Google Scholar 

  3. Paterson GK, Harrison EM, Holmes MA (2014) The emergence of mecC methicillin-resistant Staphylococcus aureus. Trends Microbiol 22:42–47. https://doi.org/10.1016/j.tim.2013.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sidairi HA, Reid EK, LeBlanc JJ, Sandila N, Head J, Davis I, Bonnar P (2023) Optimizing treatment of Staphylococcus aureus Bloodstream infections following rapid molecular diagnostic testing and an antimicrobial stewardship program intervention. Microbiol Spectr 19:1592–1601. https://doi.org/10.1128/spectrum.01648-22

    Article  CAS  Google Scholar 

  5. Kumar G, Kiran Tudu A (2023) Tackling multidrug-resistant Staphylococcus aureus by natural products and their analogues acting as NorA efflux pump inhibitors. Bioorg Med Chem 80:1–20. https://doi.org/10.1016/j.bmc.2023.117187

    Article  CAS  Google Scholar 

  6. Li B, Webster TJ (2018) Bacteria antibiotic resistance: new challenges and opportunities for implant-associated orthopedic infections. J Orthop Res 36:22–32. https://doi.org/10.1002/jor.23656

    Article  PubMed  Google Scholar 

  7. Becker K, van Alen S, Idelevich EA, Schleimer N, Seggewiss J, Mellmann A, Kaspar U, Peters G (2018) Plasmid-encoded transferable mecB-mediated methicillin resistance in Staphylococcus aureus. Emerg Infect Dis 24:242–248. https://doi.org/10.3201/eid2402.171074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pichon C, Felden B (2005) Small RNA genes expressed from Staphylococcus aureus genomic and pathogenicity islands with specific expression among pathogenic strains. Proc Natl Acad Sci USA 102:14249–14254. https://doi.org/10.1073/pnas.0503838102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. David MZ, Daum RS (2010) Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 23:616–687. https://doi.org/10.1128/CMR.00081-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Scherr TD, Roux CM, Hanke ML, Angle A, Dunman PM, Kielian T (2013) Global transcriptome analysis of Staphylococcus aureus biofilms in response to innate immune cells. Infect Immun 81:4363–4376. https://doi.org/10.1128/iai.00819-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shore AC, Deasy EC, Slickers P, Brennan G, O'Connell B, Monecke S, Ehricht R, Coleman DC (2011) Detection of Staphylococcal cassette chromosome mec Type XI carrying highly divergent mecA, mecI, mecR1, blaZ, and ccr genes in human clinical isolates of clonal complex 130 methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 55:3765–3773. https://doi.org/10.1128/aac.00187-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dalal V, Kumari R (2022) Screening and identification of natural product-like compounds as potential antibacterial agents targeting FemC of Staphylococcus aureus: an in-silico approach. ChemistrySelect 7:1–9. https://doi.org/10.1002/slct.202201728

    Article  CAS  Google Scholar 

  13. Kumari R, Dalal V (2022) Identification of potential inhibitors for LLM of Staphylococcus aureus: structure-based pharmacophore modeling, molecular dynamics, and binding free energy studies. J Biomol Struct Dyn 40:9833–9847. https://doi.org/10.1080/07391102.2021.1936179

    Article  CAS  PubMed  Google Scholar 

  14. Dalal V, Golemi-Kotra D, Kumar P (2022) Quantum mechanics/molecular mechanics studies on the catalytic mechanism of a novel esterase (FmtA) of Staphylococcus aureus. J Chem Inf Model 62:2409–2420. https://doi.org/10.1021/acs.jcim.2c00057

    Article  CAS  PubMed  Google Scholar 

  15. Dalal V, Kumar P, Rakhaminov G, Qamar A, Fan X, Hunter H, Tomar S, Golemi-Kotra D, Kumar P (2019) Repurposing an ancient protein core structure: structural studies on FmtA, a novel esterase of Staphylococcus aureus. J Mol Biol 431:3107–3123. https://doi.org/10.1016/j.jmb.2019.06.019

    Article  CAS  PubMed  Google Scholar 

  16. Dalal V, Dhankhar P, Singh V, Singh V, Rakhaminov G, Golemi-Kotra D, Kumar P (2021) Structure-based identification of potential drugs against FmtA of Staphylococcus aureus: virtual screening, molecular dynamics, MM-GBSA, and QM/MM. Protein J 40:148–165. https://doi.org/10.1007/s10930-020-09953-6

    Article  CAS  PubMed  Google Scholar 

  17. Kumari R, Rathi R, Pathak SR, Dalal V (2022) Structural-based virtual screening and identification of novel potent antimicrobial compounds against YsxC of Staphylococcus aureus. J Mol Struct 1255:1–11. https://doi.org/10.1016/j.molstruc.2022.132476

    Article  CAS  Google Scholar 

  18. Chen F, Di H, Wang Y, Cao Q, Xu B, Zhang X, Yang N, Liu G, Yang CG, Xu Y, Jiang H, Lian F, Zhang N, Li J, Lan L (2016) Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence. Nat Chem Biol 12:174–179. https://doi.org/10.1038/nchembio.2003

    Article  CAS  PubMed  Google Scholar 

  19. Zheng W, Liang Y, Zhao H, Zhang J, Li Z (2015) 5,5 ′-Methylenedisalicylic acid (MDSA) modulates SarA/MgrA phosphorylation by targeting Ser/Thr phosphatase Stp1. Chembiochem 16:1035–1040. https://doi.org/10.1002/cbic.201500003

    Article  CAS  PubMed  Google Scholar 

  20. Burnside K, Lembo A, Harrell MI, Gurney M, Xue L, Nguyen-Thao Binh T, Connelly JE, Jewell KA, Schmidt BZ, de los Reyes M, Tao WA, Doran KS, Rajagopal L (2011) Serine/threonine phosphatase Stp1 mediates post-transcriptional regulation of hemolysin, autolysis, and virulence of group B Streptococcus. J Biol Chem 286:44197–44210. https://doi.org/10.1074/jbc.M111.313486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cameron DR, Ward DV, Kostoulias X, Howden BP, Moellering Jr RC, Eliopoulos GM, Peleg AY (2012) Serine/threonine phosphatase Stp1 contributes to reduced susceptibility to vancomycin and virulence in Staphylococcus aureus. J Infect Dis 205:1677–1687. https://doi.org/10.1093/infdis/jis252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zheng WH, Cai XD, Xie MS, Liang YJ, Wang T, Li ZG (2016) Structure-based identification of a potent inhibitor targeting Stp1-mediated virulence regulation in Staphylococcus aureus. Cell Chem Biol 23:1002–1013. https://doi.org/10.1016/j.chembiol.2016.06.014

    Article  CAS  PubMed  Google Scholar 

  23. Liu T-t, Yang T, Gao M-n, Chen K-x, Yang S, Yu K-q, Jiang H-l (2019) The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations. Acta Pharmacol Sin 40:850–858. https://doi.org/10.1038/s41401-019-0216-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Murthy HN, Kim YS, Park SY, Paek KY (2014) Biotechnological production of caffeic acid derivatives from cell and organ cultures of Echinacea species. Appl Microbiol Biotechnol 98:7707–7717. https://doi.org/10.1007/s00253-014-5962-6

    Article  CAS  PubMed  Google Scholar 

  25. Chen W, Lin H-R, Wei C-M, Luo X-H, Sun M-L, Yang Z-Z, Chen X-Y, Wang H-B (2018) Echinacoside, a phenylethanoid glycoside from Cistanche deserticola, extends lifespan of Caenorhabditis elegans and protects from Aβ-induced toxicity. Biogerontology 19:47–65. https://doi.org/10.1007/s10522-017-9738-0

    Article  CAS  PubMed  Google Scholar 

  26. Xiong WT, Gu L, Wang C, Sun HX, Liu X (2013) Anti-hyperglycemic and hypolipidemic effects of Cistanche tubulosa in type 2 diabetic db/db mice. J Ethnopharmacol 150:935–945. https://doi.org/10.1016/j.jep.2013.09.027

    Article  PubMed  Google Scholar 

  27. Macková A, Mucaji P, Widowitz U, Bauer R (2013) In vitro anti-inflammatory activity of Ligustrum vulgare extracts and their analytical characterization. Nat Prod Commun 8:1509–1512. https://doi.org/10.1177/1934578X1300801102

    Article  PubMed  Google Scholar 

  28. Dong L, Yu D, Wu N, Wang H, Niu J, Wang Y, Zou Z (2015) Echinacoside induces apoptosis in human SW480 colorectal cancer cells by induction of oxidative DNA damages. Int J Mol Sci 16:14655–14668. https://doi.org/10.3390/ijms160714655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chuang HW, Wang TY, Huang CC, Wei IH (2022) Echinacoside exhibits antidepressant-like effects through AMPAR-Akt/ERK-mTOR pathway stimulation and BDNF expression in mice. Chin Med 17:1–12. https://doi.org/10.1186/s13020-021-00549-5

    Article  CAS  Google Scholar 

  30. Yang Y, Wang X, Gao Y, Wang H, Niu X (2021) Insight into the dual inhibitory mechanism of verbascoside targeting serine/threonine phosphatase Stp1 against Staphylococcus aureus. Eur J Pharm Sci 157:1–11. https://doi.org/10.1016/j.ejps.2020.105628

    Article  CAS  Google Scholar 

  31. Gao YW, Wang HS, Li XN, Niu XD (2023) Molecular mechanism of green tea polyphenol epicatechin gallate attenuating Staphylococcus aureus pathogenicity by targeting Ser/Thr phosphatase Stp1. Food Funct 14:4792–4806. https://doi.org/10.1039/d3fo00170a

    Article  CAS  PubMed  Google Scholar 

  32. Song M, Li L, Li M, Cha YH, Deng XM, Wang JF (2016) Apigenin protects mice from pneumococcal pneumonia by inhibiting the cytolytic activity of pneumolysin. Fitoterapia 115:31–36. https://doi.org/10.1016/j.fitote.2016.09.017

    Article  CAS  PubMed  Google Scholar 

  33. Teng Z, Shi D, Liu H, Shen Z, Zha Y, Li W, Deng X, Wang J (2017) Lysionotin attenuates Staphylococcus aureus pathogenicity by inhibiting alpha-toxin expression. Appl Microbiol Biotechnol 101:6697–6703. https://doi.org/10.1007/s00253-017-8417-z

    Article  CAS  PubMed  Google Scholar 

  34. Vieira TF, Sousa SF (2019) Comparing AutoDock and Vina in ligand/decoy discrimination for virtual screening. Appl Sci 9:1–18. https://doi.org/10.3390/app9214538

    Article  CAS  Google Scholar 

  35. Fuhrmann J, Rurainski A, Lenhof HP, Neumann D (2010) A new Lamarckian genetic algorithm for flexible ligand-receptor docking. J Comput Chem 31:1911–1918. https://doi.org/10.1002/jcc.21478

    Article  CAS  PubMed  Google Scholar 

  36. Zayed MF, Ibrahim SRM, Habib ESE, Hassan MH, Ahmed S, Rateb HS (2019) Design, synthesis, antimicrobial and anti-biofilm evaluation, and molecular docking of newly substituted fluoroquinazolinones. Med Chem 15:659–675. https://doi.org/10.2174/1573406414666181109092944

    Article  CAS  PubMed  Google Scholar 

  37. Wang X, Yang Y, Gao Y, Niu X (2020) Discovery of the novel inhibitor against New Delhi metallo-β-lactamase based on virtual screening and molecular modelling. Int J Mol Sci 21:1–14. https://doi.org/10.3390/ijms21103567

    Article  CAS  Google Scholar 

  38. Nhung NT, Duong N, Phung HTT, Vo QV, Tam NM (2022) In silico screening of potential β-secretase (BACE1) inhibitors from VIETHERB database. J Mol Model 28:1–10. https://doi.org/10.1007/s00894-022-05051-9

    Article  CAS  Google Scholar 

  39. Panteva MT, Giambasu GM, York DM (2015) Force field for Mg2+, Mn2+, Zn2+, and Cd2+ ions that have balanced interactions with nucleic acids. J Phys Chem B 119:15460–15470. https://doi.org/10.1021/acs.jpcb.5b10423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zarezade V, Abolghasemi M, Rahim F, Veisi A, Behbahani M (2018) In silico assessment of new progesterone receptor inhibitors using molecular dynamics: a new insight into breast cancer treatment. J Mol Model 24:1–19. https://doi.org/10.1007/s00894-018-3858-6

    Article  CAS  Google Scholar 

  41. Eftink MR, Ghiron CA (1981) Fluorescence quenching studies with proteins. Anal Biochem 114:199–227. https://doi.org/10.1016/0003-2697(81)90474-7

    Article  CAS  PubMed  Google Scholar 

  42. Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:1–13. https://doi.org/10.1038/srep42717

    Article  Google Scholar 

  43. Çalışkaner ZO (2022) Computational discovery of novel inhibitory candidates targeting versatile transcriptional repressor MBD2. J Mol Model 28:1–17. https://doi.org/10.1007/s00894-022-05297-3

    Article  CAS  Google Scholar 

  44. Singh V, Dhankhar P, Dalal V, Tomar S, Golemi-Kotra D, Kumar P (2022) Drug-repurposing approach to combat Staphylococcus aureus: biomolecular and binding interaction study. ACS Omega 7:38448–38458. https://doi.org/10.1021/acsomega.2c03671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang T, Liu T, Gan J, Yu K, Chen K, Xue W, Lan L, Yang S, Yang C-G (2019) Structural insight into the mechanism of Staphylococcus aureus Stp1 phosphatase. ACS Infect Dis 5:841–850. https://doi.org/10.1021/acsinfecdis.8b00316

    Article  CAS  PubMed  Google Scholar 

  46. Liu J, Yang L, Dong Y, Zhang B, Ma X (2018) Echinacoside, an inestimable natural product in treatment of neurological and other disorders. Molecules 23:1–23. https://doi.org/10.3390/molecules23051213

    Article  CAS  Google Scholar 

  47. Li F, Yang X, Yang Y, Li P, Yang Z, Zhang C (2015) Phospholipid complex as an approach for bioavailability enhancement of echinacoside. Drug Dev Ind Pharm 41:1777–1784. https://doi.org/10.3109/03639045.2015.1004183

    Article  CAS  PubMed  Google Scholar 

  48. Shen JY, Yang XL, Yang ZL, Kou JP, Li F (2015) Enhancement of absorption and bioavailability of echinacoside by verapamil or clove oil. Drug Des Devel Ther 9:4685–4693. https://doi.org/10.2147/dddt.s87581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang X, Li F, Yang Y, Shen J, Zou R, Zhu P, Zhang C, Yang Z, Li P (2013) Efficacy and safety of echinacoside in a rat osteopenia model. Evid Based Complement Alternat Med 2013:1–11. https://doi.org/10.1155/2013/926928

    Article  Google Scholar 

  50. Wu Y, Li L, Wen T, Li Y-Q (2007) Protective effects of echinacoside on carbon tetrachloride-induced hepatotoxicity in rats. Toxicology 232:50–56. https://doi.org/10.1016/j.tox.2006.12.013

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was sponsored by Qing Lan Project of Jiangsu Province in 2023 and the Doctoral Promotion Program Research Initiation Fund of Suzhou Polytechnic Institute of Agriculture (grant no. BS[2022]21).

Author information

Authors and Affiliations

  1. Faculty of Food Science and Technology, Suzhou Polytechnic Institute of Agriculture, Suzhou, 215008, China

    Peng Xie, Yue Gao, Chenqi Wu & Yanan Yang

  2. College of Food Science and Engineering, Jilin Agricultural University, Changchun, 130118, Jilin, China

    Xuenan Li

Authors
  1. Peng Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chenqi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuenan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Peng Xie: conceptualization, methodology, funding acquisition, and writing—original draft. Yue Gao: data curation, validation, investigation, and resources. Chenqi Wu: formal analysis, conceptualization, and methodology. Xuenan Li: investigation, software, and data curation. Yanan Yang: funding acquisition, supervision, and writing—review and editing.

Corresponding author

Correspondence to Yanan Yang.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOC 645 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, P., Gao, Y., Wu, C. et al. The inhibitory mechanism of echinacoside against Staphylococcus aureus Ser/Thr phosphatase Stp1 by virtual screening and molecular modeling. J Mol Model 29, 320 (2023). https://doi.org/10.1007/s00894-023-05723-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-023-05723-0

Keywords

Search

Navigation