High efficiency drug repurposing design for new antifungal agents

Jong H. Kim, Kathleen L. Chan, Luisa W. Cheng, Lisa A. Tell, Barbara A. Byrne, Kristin A Clothier, Kirkwood M. Land

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated “chemosensitization” as a method to improve the efficiency of antifungal drug repurposing, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent chemosensitizers to enhance antifungal activity of the repurposed drug bithionol. Of note, inclusion of fungal mutants, such as antioxidant mutants, could also facilitate drug repurposing efficiency, which is reflected in the enhancement of antifungal efficacy of bithionol. Bithionol overcame antifungal (viz., fludioxonil) tolerance of the antioxidant mutants of the human/animal pathogen Aspergillus fumigatus. Altogether, our strategy can lead to the development of a high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abates drug or fungicide resistance.

Original languageEnglish (US)
Article number31
Pages (from-to)1-14
Number of pages14
JournalMethods and Protocols
Volume2
Issue number2
DOIs
StatePublished - 2019

Keywords

  • Antifungal intervention
  • Antioxidant system
  • Aspergillus
  • Chemosensitization
  • Drug repurposing
  • Drug resistance
  • Mutants
  • Pathogen control

ASJC Scopus subject areas

  • Biotechnology
  • Structural Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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