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

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, o...

Full description

Saved in:
Bibliographic Details
Published inMedical microbiology and immunology Vol. 203; no. 5; pp. 341 - 355
Main Authors Boros-Majewska, Joanna, Salewska, Natalia, Borowski, Edward, Milewski, Sławomir, Malic, Sladjana, Wei, Xiao-Qing, Hayes, Anthony J., Wilson, Melanie J., Williams, David W.
Format Journal Article
LanguageEnglish
Published Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2014
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary: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 A 1 , 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 A 1 had lower minimal inhibitory concentration than novel derivatives. However, Nystatin A 1 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 A 1 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 A 1 . Furthermore, compared with Nystatin A 1 , 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.
ISSN:0300-8584
1432-1831
DOI:10.1007/s00430-014-0343-4