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Medical Microbiology and Immunology

, Volume 203, Issue 5, pp 341–355 | Cite as

Novel Nystatin A1 derivatives exhibiting low host cell toxicity and antifungal activity in an in vitro model of oral candidosis

  • Joanna Boros-Majewska
  • Natalia Salewska
  • Edward Borowski
  • Sławomir Milewski
  • Sladjana Malic
  • Xiao-Qing Wei
  • Anthony J. Hayes
  • Melanie J. Wilson
  • David W. WilliamsEmail author
Original Investigation

Abstract

Opportunistic oral infections caused by Candida albicans are frequent problems in immunocompromised patients. Management of such infections is limited due to the low number of antifungal drugs available, their relatively high toxicity and the emergence of antifungal resistance. Given these issues, our investigations have focused on novel derivatives of the antifungal antibiotic Nystatin A1, generated by modifications at the amino group of this molecule. The aims of this study were to evaluate the antifungal effectiveness and host cell toxicity of these new compounds using an in vitro model of oral candidosis based on a reconstituted human oral epithelium (RHOE). Initial studies employing broth microdilution, revealed that against planktonic C. albicans, Nystatin A1 had lower minimal inhibitory concentration than novel derivatives. However, Nystatin A1 was also markedly more toxic against human keratinocyte cells. Interestingly, using live/dead staining to assess C. albicans and tissue cell viability after RHOE infection, Nystatin A1 derivatives were more active against Candida with lower toxicity to epithelial cells than the parent drug. Lactate dehydrogenase activity released by the RHOE indicated a fourfold reduction in tissue damage when certain Nystatin derivatives were used compared with Nystatin A1. Furthermore, compared with Nystatin A1, colonisation of the oral epithelium by C. albicans was notably reduced by the new polyenes. In the absence of antifungal agents, confocal laser scanning microscopy showed that C. albicans extensively invaded the RHOE. However, the presence of the novel derivatives greatly reduced or totally prevented this fungal invasion.

Keywords

Candida albicans Antifungals Nystatin A1 Candidosis Oral infections Cytotoxicity 

Notes

Acknowledgments

We would like to thank Mrs Kath Allsopp for processing and sectioning tissue samples. We are also grateful to Mr Marc Isaacs for his assistance with confocal laser scanning microscopy. The project was financed by the National Science Centre (Poland) based on the Grant no. DEC-2011/01/N/NZ1/05269 (PRELUDIUM: pre-doctoral grant).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Joanna Boros-Majewska
    • 1
    • 2
  • Natalia Salewska
    • 2
    • 3
  • Edward Borowski
    • 1
    • 2
  • Sławomir Milewski
    • 1
  • Sladjana Malic
    • 4
  • Xiao-Qing Wei
    • 5
  • Anthony J. Hayes
    • 6
  • Melanie J. Wilson
    • 5
  • David W. Williams
    • 5
    Email author
  1. 1.Department of Pharmaceutical Technology and BiochemistryGdańsk University of Technology (GUT)GdańskPoland
  2. 2.GdańskPoland
  3. 3.Department of Organic ChemistryGdańsk University of TechnologyGdańskPoland
  4. 4.School of Healthcare SciencesManchester Metropolitan UniversityManchesterUK
  5. 5.Tissue Engineering and Reparative Dentistry, School of DentistryCardiff UniversityCardiffUK
  6. 6.Bioimaging Unit, School of BiosciencesCardiff UniversityCardiffUK

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