Differential effects of linkers on the activity of amphiphilic tobramycin antifungals

Marina Y. Fosso, Sanjib K. Shrestha, Nishad Thamban Chandrika, Emily K. Dennis, Keith D. Green, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

As the threat associated with fungal infections continues to rise and the availability of antifungal drugs remains a concern, it becomes obvious that the need to bolster the antifungal armamentarium is urgent. Building from our previous findings of tobramycin (TOB) derivatives with antifungal activity, we further investigate the effects of various linkers on the biological activity of these aminoglycosides. Herein, we analyze how thioether, sulfone, triazole, amide, and ether functionalities affect the antifungal activity of alkylated TOB derivatives against 22 Candida, Cryptococcus, and Aspergillus species. We also evaluate their impact on the hemolysis of murine erythrocytes and the cytotoxicity against mammalian cell lines. While the triazole linker appears to confer optimal activity overall, all of the linkers incorporated into the TOB derivatives resulted in compounds that are very effective against the Cryptococcus neoformans species, with MIC values ranging from 0.48 to 3.9 µg/mL.

Original languageEnglish
Article number899
JournalMolecules
Volume23
Issue number4
DOIs
StatePublished - 2018

Bibliographical note

Funding Information:
Acknowledgments: This work was supported by NIH grant AI090048 (to S.G.-T.).

Publisher Copyright:
2018 by the authors.

Keywords

  • Aminoglycosides
  • Aspergillus
  • Candida
  • Cryptococcus
  • Cytotoxicity
  • Hemolysis

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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