Skip to main content
SpringerLink
Log in

Improved Activity of Rifampicin Against Biofilms of Staphylococcus aureus by Multicomponent Complexation

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The aim of this study was to evaluate a multicomponent complex (MC) between rifampicin (RIF), β-cyclodextrin (β-CD), and selected amino acids to enhance the solubility and antibiofilm activity of RIF. After performing phase-solubility studies that demonstrated a considerable increase in the solubility of RIF for the MC, the corresponding solid system was prepared by a freeze-drying method. Characterization of the MC was performed by Fourier transform-infrared spectroscopy, thermal analysis, powder X-ray diffraction, and scanning electron microscopy. Structural analyses evidenced molecular interactions between the components, resulting in a MC with amorphous solid features. Structural studies involving both experimental (i.e., 1H NMR) and theoretical (i.e., molecular modeling) methodologies demonstrated the inclusion of the RIF piperazine ring in the β-CD cavity. The bioactivity of the MC measured against biofilms of Staphylococcus aureus showed a significant reduction in the metabolic activity of the bacterium. Overall, the studied MC exhibited promising properties for the development of pharmaceutical formulations to treat bacterial infections.

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
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Kumar A, Alam A, Rani M, Ehtesham NZ, Hasnain SE. Biofilms: survival and defense strategy for pathogens. Int J Med Microbiol. 2017;307(8):481–9. https://doi.org/10.1016/j.ijmm.2017.09.016.

    Article  CAS  PubMed  Google Scholar 

  2. Yan J, Bassler BL. Surviving as a community: antibiotic tolerance and persistence in bacterial biofilms. Cell Host Microbe. 2019;26(1):15–21. https://doi.org/10.1016/j.chom.2019.06.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Flemming H-C, Wingender J, Szewzyk U, Steinberg P, Rice SA, Kjelleberg S. Biofilms: an emergent form of bacterial life. Nat Rev Microbiol. 2016;14(9):563–75. https://doi.org/10.1038/nrmicro.2016.94.

    Article  CAS  PubMed  Google Scholar 

  4. Archer NK, Mazaitis MJ, William Costerton J, Leid JG, Powers ME, Shirtliff ME. Staphylococcus aureus biofilms: properties, regulation and roles in human disease. Virulence. 2011;2(5):445–59. https://doi.org/10.4161/viru.2.5.17724.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jolivet-Gougeon A, Bonnaure-Mallet M. Biofilms as a mechanism of bacterial resistance. Drug Discov Today Technol. 2014;11(1):49–56. https://doi.org/10.1016/j.ddtec.2014.02.003.

    Article  PubMed  Google Scholar 

  6. Wicher B, Pyta K, Przybylski P, Gdaniec M. Solvates of Zwitterionic rifampicin: recurring packing motifs via nonspecific interactions. Crystal Growth and Design. 2018;18(2):742–54. https://doi.org/10.1021/acs.cgd.7b01121.

    Article  CAS  Google Scholar 

  7. de Pinho Pessoa Nogueira L, De Oliveira YS, de C Fonseca J, Costa WS, Raffin FN, Ellena J, et al. Crystalline structure of the marketed form of Rifampicin: a case of conformational and charge transfer polymorphism. J Mol Struct. 2018;1155:260–6. https://doi.org/10.1016/j.molstruc.2017.10.083.

    Article  CAS  Google Scholar 

  8. Shishoo CJ, Shah SA, Rathod IS, Savale SS, Vora MJ. Impaired bioavailability of rifampicin in presence of isoniazid from fixed dose combination (FDC) formulation. Int J Pharm. 2001;228(1–2):53–67. https://doi.org/10.1016/S0378-5173(01)00831-6.

    Article  CAS  PubMed  Google Scholar 

  9. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015;5(5):442–53. https://doi.org/10.1016/j.apsb.2015.07.003.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations I: structure and physicochemical properties, formation of complexes, and types of complex. Drug Discov Today. 2016;21(2):356–62. https://doi.org/10.1016/j.drudis.2015.11.017.

    Article  CAS  PubMed  Google Scholar 

  11. Carrier RL, Miller LA, Ahmed I. The utility of cyclodextrins for enhancing oral bioavailability. J Control Release. 2007;123(2):78–99. https://doi.org/10.1016/j.jconrel.2007.07.018.

    Article  CAS  PubMed  Google Scholar 

  12. Barbosa JAA, Zoppi A, Quevedo MA, de Melo PN, de Medeiros ASA, Streck L, et al. Triethanolamine stabilization of methotrexate-β-cyclodextrin interactions in ternary complexes. Int J Mol Sci. 2014;15(9):17077–99. https://doi.org/10.3390/ijms150917077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. de Medeiros ASA, Zoppi A, Barbosa EG, Oliveira JIN, Fernandes-Pedrosa MF, Longhi MR, et al. Supramolecular aggregates of oligosaccharides with co-solvents in ternary systems for the solubilizing approach of triamcinolone. Carbohydr Polym. 2016;151:1040–51. https://doi.org/10.1016/j.carbpol.2016.06.044.

    Article  CAS  PubMed  Google Scholar 

  14. De Melo PN, Barbosa EG, De Caland LB, Carpegianni H, Garnero C, Longhi M, et al. Host-guest interactions between benznidazole and beta-cyclodextrin in multicomponent complex systems involving hydrophilic polymers and triethanolamine in aqueous solution. J Mol Liq. 2013;186:147–56.

    Article  Google Scholar 

  15. Miranda JA, Garnero C, Zoppi A, Sterren V, Ayala AP, Longhi MR. Characterization of systems with amino-acids and oligosaccharides as modifiers of biopharmaceutical properties of furosemide. J Pharm Biomed Anal. 2018;149:143–50. https://doi.org/10.1016/j.jpba.2017.10.038.

    Article  CAS  PubMed  Google Scholar 

  16. Aiassa V, Zoppi A, Albesa I, Longhi MR. Inclusion complexes of chloramphenicol with β-cyclodextrin and aminoacids as a way to increase drug solubility and modulate ROS production. Carbohydr Polym. 2015;121:320–7. https://doi.org/10.1016/j.carbpol.2014.11.017.

    Article  CAS  PubMed  Google Scholar 

  17. Aiassa V, Zoppi A, Becerra MC, Albesa I, Longhi MR. Enhanced inhibition of bacterial biofilm formation and reduced leukocyte toxicity by chloramphenicol:β-cyclodextrin:N-acetylcysteine complex. Carbohydr Polym. 2016;152:672–8. https://doi.org/10.1016/j.carbpol.2016.07.013.

    Article  CAS  PubMed  Google Scholar 

  18. Cerutti JP, Quevedo MA, Buhlman N, Longhi MR, Zoppi A. Synthesis and characterization of supramolecular systems containing nifedipine, β-cyclodextrin and aspartic acid. Carbohydr Polym. 2019;205:480–7. https://doi.org/10.1016/j.carbpol.2018.10.038.

    Article  CAS  PubMed  Google Scholar 

  19. Zoppi A, Buhlman N, Cerutti JP, Longhi MR, Aiassa V. Influence of proline and β-Cyclodextrin in ketoconazole physicochemical and microbiological performance. J Mol Struct. 2019;1176:470–7. https://doi.org/10.1016/j.molstruc.2018.08.094.

    Article  CAS  Google Scholar 

  20. Angiolini L, Agnes M, Cohen B, Yannakopoulou K, Douhal A. Formation, characterization and pH dependence of rifampicin: heptakis(2,6-di-O-methyl)-β-cyclodextrin complexes. Int J Pharm. 2017;531(2):668–75. https://doi.org/10.1016/j.ijpharm.2017.06.015.

    Article  CAS  PubMed  Google Scholar 

  21. Chadha R, Saini A, Gupta S, Arora P, Thakur D, Jain DVS. Encapsulation of rifampicin by natural and modified β-cyclodextrins: characterization and thermodynamic parameters. J Incl Phenom Macro. 2010;67(1–2):109–16. https://doi.org/10.1007/s10847-009-9682-y.

    Article  CAS  Google Scholar 

  22. Ferreira DA, Ferreira AG, Vizzotto L, Federman Neto A, De Oliveira AG. Analysis of the molecular association of rifampicin with hydroxypropyl-β-cyclodextrin. Revista Brasileira de Ciencias Farmaceuticas/Brazilian Journal of Pharmaceutical Sciences. 2004;40(1):43–51. https://doi.org/10.1590/S1516-93322004000100008.

    Article  CAS  Google Scholar 

  23. He D, Deng P, Yang L, Tan Q, Liu J, Yang M, et al. Molecular encapsulation of rifampicin as an inclusion complex of hydroxypropyl-β-cyclodextrin: design; characterization and in vitro dissolution. Colloids Surf B Biointerfaces. 2013;103:580–5. https://doi.org/10.1016/j.colsurfb.2012.10.062.

    Article  CAS  PubMed  Google Scholar 

  24. Rao BP, Suresh S, Narendra C, Balasangameshwer. Physicochemical characterization of β-cyclodextrin and hydroxy ethyl β-cyclodextrin complexes of rifampicin. Ars Pharmaceutica. 2006;47(1):37–59.

    Google Scholar 

  25. Tewes F, Brillault J, Couet W, Olivier JC. Formulation of rifampicin-cyclodextrin complexes for lung nebulization. J Control Release. 2008;129(2):93–9. https://doi.org/10.1016/j.jconrel.2008.04.007.

    Article  CAS  PubMed  Google Scholar 

  26. Higuchi T, Connors KA. Phase-solubility techniques. Adv Anal Chem Instr. 1965;4:117–212.

    CAS  Google Scholar 

  27. MarvinSketch. MarvinSketch v.16.2.15. ChemAxon Ltd. 2017.

  28. Frisch MJ, Trucks G, Schlegel HB, Scuseria G, Robb M, Cheeseman J, et al. Gaussian 09, revision A. 1. Gaussian Inc, Wallingford, CT. 2009;27:34.

  29. Morris GM, Ruth H, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. Software news and updates AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785–91. https://doi.org/10.1002/jcc.21256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kirschner KN, Yongye AB, Tschampel SM, González-Outeiriño J, Daniels CR, Foley BL, et al. GLYCAM06: a generalizable biomolecular force field. Carbohydrates. J Comput Chem. 2008;29(4):622–55. https://doi.org/10.1002/jcc.20820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. Development and testing of a general Amber force field. J Comput Chem. 2004;25(9):1157–74. https://doi.org/10.1002/jcc.20035.

    Article  CAS  PubMed  Google Scholar 

  32. Case DA, Cerutti DS, Cheatham Iii TE, Darden TA, Duke RE, Giese TJ, et al. AMBER 2018. University of California, San Francisco 2018.

  33. Miller BR 3rd, McGee TD Jr, Swails JM, Homeyer N, Gohlke H, Roitberg AE. MMPBSA.py: an efficient program for end-state free energy calculations. J Chem Theory Comput. 2012;8(9):3314–21. https://doi.org/10.1021/ct300418h.

    Article  CAS  PubMed  Google Scholar 

  34. Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–8.

    Article  CAS  PubMed  Google Scholar 

  35. Paixão P, Gouveia LF, Silva N, Morais JAG. Evaluation of dissolution profile similarity—comparison between the F2, the multivariate statistical distance and the F2 bootstrapping methods. Eur J Pharm Biopharm. 2017;112:67–74. https://doi.org/10.1016/j.ejpb.2016.10.026.

    Article  CAS  PubMed  Google Scholar 

  36. CLSI. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. In: CSLI document M7-A7 (7th edn). Wayne: Clinical and Laboratory Standards Institute. 2012.

  37. Quevedo MA, Zoppi A. Current trends in molecular modeling methods applied to the study of cyclodextrin complexes. J Incl Phenom Macro. 2018;90(1–2). https://doi.org/10.1007/s10847-017-0763-z.

Download references

Acknowledgments

We are grateful to Ashland Argentina S.R.L. for its donation of β-cyclodextrin. We also thank Dr. Gloria Bonetto and Mg. Norma Maggia for NMR and thermal analysis measurements, respectively.

Funding

The authors wish to acknowledge the assistance of the Universidad Nacional de Córdoba, Fondo para la Investigación Científica y Tecnológica (FONCyT) Préstamo BID PICT 2013-2150, the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECyT), and the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), which provided support and facilities for this work.

Author information

Authors and Affiliations

  1. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica, UNITEFA-CONICET, Facultad de Ciencias Químicas, Departamento de Ciencias Farmacéuticas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, s/n. Ciudad Universitaria, X5000HUA, Córdoba, Argentina

    Antonella V. Dan Córdoba, Virginia Aiassa, Marcela R. Longhi, Mario A. Quevedo & Ariana Zoppi

Authors
  1. Antonella V. Dan Córdoba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Virginia Aiassa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcela R. Longhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mario A. Quevedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ariana Zoppi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ariana Zoppi.

Ethics declarations

Conflict of Interest

A.Z., M.A.Q, M.R.L., and V.A. are career research members of CONICET.

Additional information

Publisher’s Note

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

Electronic supplementary material

ESM 1

(PDF 1350 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dan Córdoba, A.V., Aiassa, V., Longhi, M.R. et al. Improved Activity of Rifampicin Against Biofilms of Staphylococcus aureus by Multicomponent Complexation. AAPS PharmSciTech 21, 163 (2020). https://doi.org/10.1208/s12249-020-01706-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-020-01706-z

KEY WORDS

Search

Navigation