Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans

Abstract

Abstract

Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent. We recently showed that copper supplementation potentiates the activity of the azole antifungal fluconazole against the opportunistic fungal pathogen C. albicans. Here, we report eight new azole analogues derived from fluconazole in which one triazole group has been replaced with a metal-binding group, a strategy designed to enhance potentiation of azole antifungal activity by copper. The bioactivity of all eight compounds was tested and compared to that of fluconazole. Three of the analogues showed activity against C. albicans and two had lower levels of trailing growth. One compound, Flu-TSCZ, was found to impact the levels, speciation, and bioavailability of cellular metals.

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Acknowledgements

We thank Prof. Val Culotta (Johns Hopkins University, Baltimore, MD) for providing the two strains of C. albicans (KC2 and crp1Δ/Δ), Prof. Alistair Brown (University of Exeter, Exeter, UK) for providing the SC5314 and ctr1Δ/Δ strains of C. albicans, and Prof. Dennis Thiele (Duke University, Durham, NC) for providing the two strains of C. neoformans (WT H99 and ctr1Δ ctr4Δ). This work was supported by the National Institutes of Health (Grant GM084176). E. W. H. acknowledges support from the United States Department of Education GAANN Fellowship (Award No. P200A150114).

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Correspondence to Katherine J. Franz.

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Hunsaker, E.W., McAuliffe, K.J. & Franz, K.J. Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans. J Biol Inorg Chem 25, 729–745 (2020). https://doi.org/10.1007/s00775-020-01796-x

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Keywords

  • Antifungal
  • Azole
  • Copper
  • Metals in medicine
  • Candida albicans
  • Homeostasis