Skip to main content
SpringerLink
Log in

Evaluation of the inhibitory effect of isopulegol (ISO) and its β-cyclodextrin inclusion complex (ISO/β-CD) on the reversal of Staphylococcus aureus efflux pump activity

  • ORIGINAL PAPER
  • Published:
Polymer Bulletin Aims and scope Submit manuscript

Abstract

Staphylococcus aureus is known to be a human pathogen and is often resistant to antibiotics, so there is a demand for new treatment alternatives that have the ability to reverse such resistance. The present study aimed to evaluate the antibacterial action and reversal of the efflux pump activity of the compounds Isopulegol (ISO) and its β-cyclodextrin inclusion complex (ISO/β-CD) in S. aureus strains carrying an efflux pump. (MsrA, TetK, NorA and MepA). The complex was obtained using the paste complexation method. The minimum inhibitory concentration (MIC) of ISO and ISO/β-CD was determined for the evaluation of antibacterial activity against multiresistant strains of S. aureus (RN4220, IS-58, 1199, 1199B and K2068) and the compounds showed a minimum inhibitory concentration (MIC) ≥ 1024 μg/mL. Modulation assays were performed using ISO and ISO/β-CD, which associated with antibiotics and Ethidium Bromide (EtBr) showed synergism and MIC reduction in some of the tested bacteria. Therefore, it can be concluded that the isolated compounds ISO and ISO/β-CD are effective in inhibiting the efflux pump mechanism against some of the tested strains; with modulation, only strains IS-58, SA 1199 and K2068 showed a MIC decrease effect, while all strains showed a reduction in MIC with ethidium bromide.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Explore related subjects

Discover the latest articles, news and stories from top researchers in related subjects.

References

  1. Tantawy E, Schwermann N, Ostermeier T et al (2022) Staphylococcus aureus Multiplexes death-effector deoxyribonucleosides to neutralize phagocytes. Front Immunol 13:847171. https://doi.org/10.3389/FIMMU.2022.847171/BIBTEX

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. da Silva AC, Rodrigues MX, Silva NCC (2019) Methicillin-resistant Staphylococcus aureus in food and the prevalence in Brazil: a review. Braz J Microbiol 51:347–356. https://doi.org/10.1007/S42770-019-00168-1

    Article  PubMed  PubMed Central  Google Scholar 

  3. Micoli F, Bagnoli F, Rappuoli R, Serruto D (2021) The role of vaccines in combatting antimicrobial resistance. Nat. Rev. Microbiol. 19:287–302. https://doi.org/10.1038/s41579-020-00506-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jeon K, Kim JM, Rho K et al (2022) Performance of a machine learning-based methicillin resistance of Staphylococcus aureus identification system using MALDI-TOF MS and comparison of the accuracy according to SCCmec types. Microorganisms 10:1903. https://doi.org/10.3390/MICROORGANISMS10101903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McGuinness WA, Malachowa N, DeLeo FR (2017) Vancomycin resistance in Staphylococcus aureus strains. Yale J Biol Med 90:269–281

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Parastan R, Kargar M, Solhjoo K, Kafilzadeh F (2020) Staphylococcus aureus biofilms: structures, antibiotic resistance, inhibition, and vaccines. Gene Rep 20:100739. https://doi.org/10.1016/J.GENREP.2020.100739

    Article  CAS  Google Scholar 

  7. Uddin TM, Chakraborty AJ, Khusro A et al (2021) Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. J Infect Public Health 14:1750–1766. https://doi.org/10.1016/J.JIPH.2021.10.020

    Article  PubMed  Google Scholar 

  8. dos Santos JFS, Tintino SR, de Freitas TS et al (2018) In vitro e in silico evaluation of the inhibition of Staphylococcus aureus efflux pumps by caffeic and gallic acid. Comp Immunol Microbiol Infect Dis 57:22–28. https://doi.org/10.1016/j.cimid.2018.03.001

    Article  PubMed  Google Scholar 

  9. Andrade Próspero DF, Reis Filho AC, Piauilino CA et al (2018) Effects of isopulegol in acute nociception in mice: possible involvement of muscarinic receptors, opioid system and L-arginine/NO/cGMP pathway. Chem Biol Interact 293:55–60. https://doi.org/10.1016/j.cbi.2018.07.019

    Article  CAS  PubMed  Google Scholar 

  10. dos Passos MP, Dória GAA, de Souza Araújo AA et al (2016) Docking and physico-chemical properties of α- and β-cyclodextrin complex containing isopulegol: a comparative study. J Incl Phenom Macrocycl Chem 85:341–354. https://doi.org/10.1007/s10847-016-0633-0

    Article  CAS  Google Scholar 

  11. Ramos AGB, de Menezes IRA, da Silva MSA et al (2020) Antiedematogenic and anti-inflammatory activity of the Monoterpene isopulegol and Its -Cyclodextrin ( -CD) inclusion complex in animal inflammation models. Foods 9:1–16. https://doi.org/10.3390/foods9050630

    Article  CAS  Google Scholar 

  12. Andrade TA, Freitas TS, Araújo FO et al (2017) Physico-chemical characterization and antibacterial activity of inclusion complexes of Hyptis martiusii Benth essential oil in β-cyclodextrin. Biomed Pharmacother 89:201–207. https://doi.org/10.1016/j.biopha.2017.01.158

    Article  CAS  PubMed  Google Scholar 

  13. Javadpour MM, Juban MM, Lo WCJ et al (1996) De novo antimicrobial peptides with low mammalian cell toxicity. J Med Chem 39:3107–3113. https://doi.org/10.1021/jm9509410

    Article  CAS  PubMed  Google Scholar 

  14. CLSI (2013) Performance standards for Performance standards for antimicrobial susceptibility testing; 23rd informational supplement. Clinical and Laboratory Standards Institute. CLSI M10U0-S21

  15. Coutinho HDM, Costa JGM, Lima EO et al (2008) Enhancement of the antibiotic activity against a multiresistant Escherichia coli by Mentha arvensis L. and chlorpromazine. Chemotherapy 54:328–330. https://doi.org/10.1159/000151267

    Article  CAS  PubMed  Google Scholar 

  16. Kowalska-Krochmal B, Dudek-Wicher R (2021) The minimum inhibitory concentration of antibiotics: methods, interpretation, Clinical Relevance. Pathogens 5(10):165. https://doi.org/10.3390/PATHOGENS10020165

    Article  Google Scholar 

  17. Naigre R, Kalck P, Roques C et al (1996) Comparison of antimicrobial properties of monoterpenes and their carbonylated products. Planta Med 62:275–277. https://doi.org/10.1055/s-2006-957877

    Article  CAS  PubMed  Google Scholar 

  18. Trapani A, Catalano A, Carocci A et al (2019) Effect of Methyl-β-Cyclodextrin on the antimicrobial activity of a new series of poorly water-soluble benzothiazoles. Carbohydr Polym 207:720–728. https://doi.org/10.1016/j.carbpol.2018.12.016

    Article  CAS  PubMed  Google Scholar 

  19. Braga Ribeiro AM, de Sousa JN, Costa LM et al (2019) Antimicrobial activity of Phyllanthus amarus Schumach. & Thonn and inhibition of the NorA efflux pump of Staphylococcus aureus by Phyllanthin. Microb Pathog 130:242–246. https://doi.org/10.1016/j.micpath.2019.03.012

    Article  CAS  PubMed  Google Scholar 

  20. de Morais Oliveira-Tintino CD, Tintino SR, Limaverde PW et al (2018) Inhibition of the essential oil from Chenopodium ambrosioides L. and α-terpinene on the NorA efflux-pump of Staphylococcus aureus. Food Chem 262:72–77. https://doi.org/10.1016/j.foodchem.2018.04.040

    Article  CAS  PubMed  Google Scholar 

  21. Costa MDS, Rocha JE, Campina FF et al (2019) Comparative analysis of the antibacterial and drug-modulatory effect of D-limonene alone and complexed with β-cyclodextrin. Eur J Pharm Sci 128:158–161. https://doi.org/10.1016/j.ejps.2018.11.036

    Article  CAS  PubMed  Google Scholar 

  22. Tintino SR, Morais-Tintino CD, Campina FF et al (2017) Tannic acid affects the phenotype of Staphylococcus aureus resistant to tetracycline and erythromycin by inhibition of efflux pumps. Bioorg Chem 74:197–200. https://doi.org/10.1016/j.bioorg.2017.08.004

    Article  CAS  PubMed  Google Scholar 

  23. Couto I, Costa SS, Viveiros M et al (2008) Efflux-mediated response of Staphylococcus aureus exposed to ethidium bromide. J Antimicrob Chemother 62:504–513. https://doi.org/10.1093/jac/dkn217

    Article  CAS  PubMed  Google Scholar 

  24. Silveira ZDS, De Freitas TS, Douglas H et al (2020) Evaluation of the antibacterial activity and efflux pump reversal of thymol and carvacrol against Staphylococcus aureus and their toxicity in drosophila melanogaster. Molecules 25(9):2103. https://doi.org/10.3390/molecules25092103

    Article  CAS  Google Scholar 

  25. Cappiello F, Loffredo MR, Del PC et al (2020) The revaluation of plant-derived terpenes to fight antibiotic-resistant infections. Antibiotics 9:325. https://doi.org/10.3390/ANTIBIOTICS9060325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mahizan NA, Yang SK, Moo CL et al (2019) Terpene derivatives as a potential agent against antimicrobial resistance (AMR) pathogens. Molecules 24:2631. https://doi.org/10.3390/MOLECULES24142631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Silva Pereira RL, Campina FF, Costa MDS et al (2021) Antibacterial and modulatory activities of β-cyclodextrin complexed with (+)-β-citronellol against multidrug-resistant strains. Microb Pathog 156:104928. https://doi.org/10.1016/j.micpath.2021.104928

    Article  CAS  PubMed  Google Scholar 

  28. Pereira da Cruz R, Sampaio de Freitas T, do Socorro Costa M et al (2020) Effect of α-bisabolol and its β-cyclodextrin complex as TetK and NorA efflux pump inhibitors in Staphylococcus aureus strains. Antibiotic 9(1):28. https://doi.org/10.3390/antibiotics9010028

    Article  CAS  Google Scholar 

  29. Alcântara IS, Martins AOBPB, de Oliveira MRC et al (2022) Cytotoxic potential and antiparasitic activity of the Croton rhamnifolioides Pax leaves. & K. Hoffm essential oil and its inclusion complex (EOCr/β-CD). Polym Bull 79:1175–1185. https://doi.org/10.1007/s00289-021-03556-6

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The University Regional of Cariri, to the pharmacology and molecular chemistry and microbiology and molecular chemistry laboratories for carrying out the tests and to the development networks for all financial support.

Funding

This work was supported by Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Financiadora de Estudos e Projetos—Brasil (FINEP).

Author information

Authors and Affiliations

  1. Department of Biological Chemistry, Regional University of Cariri, Crato, CE, 63105-000, Brazil

    Lucas Yure Santos da Silva, Daniel Sampaio Alves, Andreza Guedes Barbosa Ramos, Renata Torres Pessoa, José Bezerra de Araújo-Neto, Maria Milene Costa da Silva, Isabel Sousa Alcântara, Luiz Jardelino de Lacerda Neto, Maria Rayane Correia de Oliveira, Cícera Datiane de Morais Oliveira-Tintino, Henrique Douglas Melo Coutinho & Irwin Rose Alencar de Menezes

  2. Department of Physiology, Federal University of Sergipe, São Cristóvão, Aracaju, SE, 49100-000, Brazil

    Lucindo José Quintans-Júnior

  3. Department of Agricultural and Environmental Sciences, Milan State University, 20133, Milan, Italy

    Marcello Iriti

Authors
  1. Lucas Yure Santos da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Sampaio Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreza Guedes Barbosa Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renata Torres Pessoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José Bezerra de Araújo-Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Milene Costa da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Isabel Sousa Alcântara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luiz Jardelino de Lacerda Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Rayane Correia de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cícera Datiane de Morais Oliveira-Tintino
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lucindo José Quintans-Júnior
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Henrique Douglas Melo Coutinho
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marcello Iriti
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Irwin Rose Alencar de Menezes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the conception and design of the study. Tests and data analysis were performed by LYSS, AGBR, RTP, JBAN, MMCS, CDM OT. The Isopulegol complex was provided by Professor LJQJ. The first version of the manuscript was revised by LJLN, MRCO and ISA. The final version of the manuscript was reviewed by Professors HDMC and IRAM. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Henrique Douglas Melo Coutinho, Marcello Iriti or Irwin Rose Alencar de Menezes.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

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

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

da Silva, L.Y.S., Alves, D.S., Ramos, A.G.B. et al. Evaluation of the inhibitory effect of isopulegol (ISO) and its β-cyclodextrin inclusion complex (ISO/β-CD) on the reversal of Staphylococcus aureus efflux pump activity. Polym. Bull. 81, 9933–9946 (2024). https://doi.org/10.1007/s00289-024-05191-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00289-024-05191-3

Keywords

Search

Navigation