Zinc and Iron Homeostasis: Target-Based Drug Screening as New Route for Antifungal Drug Development

Research output: Contribution to journalArticle

Colleges, School and Institutes

External organisations

  • Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
  • Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Abstract

The incidence of fungal diseases is on the rise and the number of fatalities is still unacceptably high. While advances into antifungal drug development have been made there remains an urgent need to develop novel antifungal agents targeting as-yet unexploited pathways, such as metal ion homeostasis. Here we report such an approach by developing a metal sensor screen in the opportunistic human fungal pathogen Candida albicans. Using this reporter strain, we screened a library of 1,200 compounds and discovered several active compounds not previously described as chemical entities with antifungal properties. Two of these, artemisinin and pyrvinium pamoate, have been further characterized and their interference with metal homeostasis and potential as novel antifungal compounds validated. Lastly, we demonstrate that the same strain can be used to report on intracellular conditions within host phagocytes, paving the way toward the development of novel screening platforms that could identify compounds with the potential to perturb ion homeostasis of the pathogen specifically within host cells.

Details

Original languageEnglish
Article number181
JournalFrontiers in cellular and infection microbiology
Volume9
Publication statusPublished - 29 May 2019

Keywords

  • Candida, antifungals, artemisinin, high throughput drug screening, iron homeostasis, pyrvinium pamoate, zinc homeostasis