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

Hunsaker, Elizabeth W; McAuliffe, Katherine J.; Franz, Katherine J.

doi:10.1007/s00775-020-01796-x

Cited by 9 publications

(9 citation statements)

References 61 publications

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“…Growing evidence indicates that copper potentiates the antifungal activity of fluconazole against opportunistic pathogenic yeasts (18-20). Here, we confirmed that the combination of copper and fluconazole impairs the growth of Candida glabrata at concentrations where these compounds cause only mild growth defects when used separately (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In recent years, there was a growing interest in exploiting the antifungal properties of copper. Trojan horse strategies that deceive the fungus copper homeostatic mechanisms (20, 29) or the combination of copper with available antifungals (18, 19, 59) have proved to be effective against several fungal species. In particular, copper has been shown to potentiate the activity of fluconazole (18, 19, 43), one of the most prescribed antifungals worldwide.…”

Section: Discussionmentioning

confidence: 99%

“…Inspired by the antifungal properties of copper, several authors have combined this metal with fluconazole and showed that this could be a promising strategy, since the combination resulted in greater antifungal activity (18-20). However, the mechanism underlying such synergism has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Copper Acts Synergistically with Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis

Gaspar-Cordeiro

Amaral

Pobre

et al. 2021

Preprint

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The synergistic combinations of drugs are promising strategies to boost the effectiveness of current antifungals and thus prevent the emergence of resistance. In this work, we show that copper and the antifungal fluconazole act synergistically against Candida glabrata, an opportunistic pathogenic yeast intrinsically tolerant to fluconazole. Analyses of the transcriptomic profile of C. glabrata after the combination of copper and fluconazole showed that the expression of the multidrug transporter gene CDR1 was decreased, suggesting that fluconazole efflux could be affected. In agreement, we observed that copper inhibits the transactivation of Pdr1, the transcription regulator of multidrug transporters, and leads to the intracellular accumulation of fluconazole. Copper also decreases the transcriptional induction of ergosterol biosynthesis (ERG) genes by fluconazole, which culminates in the accumulation of toxic sterols. Co-treatment of cells with copper and fluconazole should affect the function of proteins located in the plasma membrane, as several ultrastructural alterations, including irregular cell wall and plasma membrane and loss of cell wall integrity, were observed. Finally, we show that the combination of copper and fluconazole downregulates the expression of the gene encoding the zinc-responsive transcription regulator Zap1, which possibly, together with the membrane transporters malfunction, generates zinc depletion. Supplementation with zinc reverts the toxic effect of combining copper with fluconazole, underscoring the importance of this metal in the observed synergistic effect. Overall, this work, while unveiling the molecular basis that supports the use of copper to enhance the effectiveness of fluconazole, paves the way for the development of new metal-based antifungal strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Copper Acts Synergistically with Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis

Gaspar-Cordeiro

Amaral

Pobre

et al. 2021

Preprint

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“…Inspired by the antifungal properties of copper, several authors have combined this metal with fluconazole and showed that this could be a promising strategy, since the combination resulted in greater antifungal activity ( Ząbek et al, 2015 ; Hunsaker and Franz, 2019b ; Hunsaker et al, 2020 ). However, the mechanism underlying such synergism has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis

Gaspar-Cordeiro

Amaral²,

Pobre³

et al. 2022

Front. Microbiol.

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The synergistic combinations of drugs are promising strategies to boost the effectiveness of current antifungals and thus prevent the emergence of resistance. In this work, we show that copper and the antifungal fluconazole act synergistically against Candida glabrata, an opportunistic pathogenic yeast intrinsically tolerant to fluconazole. Analyses of the transcriptomic profile of C. glabrata after the combination of copper and fluconazole showed that the expression of the multidrug transporter gene CDR1 was decreased, suggesting that fluconazole efflux could be affected. In agreement, we observed that copper inhibits the transactivation of Pdr1, the transcription regulator of multidrug transporters and leads to the intracellular accumulation of fluconazole. Copper also decreases the transcriptional induction of ergosterol biosynthesis (ERG) genes by fluconazole, which culminates in the accumulation of toxic sterols. Co-treatment of cells with copper and fluconazole should affect the function of proteins located in the plasma membrane, as several ultrastructural alterations, including irregular cell wall and plasma membrane and loss of cell wall integrity, were observed. Finally, we show that the combination of copper and fluconazole downregulates the expression of the gene encoding the zinc-responsive transcription regulator Zap1, which possibly, together with the membrane transporters malfunction, generates zinc depletion. Supplementation with zinc reverts the toxic effect of combining copper with fluconazole, underscoring the importance of this metal in the observed synergistic effect. Overall, this work, while unveiling the molecular basis that supports the use of copper to enhance the effectiveness of fluconazole, paves the way for the development of new metal-based antifungal strategies.

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“…in other medicinal fields, [29][30][31][32][33][34][35][36][37][38] some groups have decided to assess the potential of such compounds to fight fungal infections. 39,40 Despite such a wealth of promising examples of metal-based drugs, there is a paucity of examples of such compounds applied in the field of antifungal therapy. Here, just sporadic reports confirmed the effectiveness of different transition metal complexes (e.g.…”

Section: Introductionmentioning

confidence: 99%

In vivo active organometallic-containing antimycotic agents

et al. 2021

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

Cited by 9 publications

References 61 publications

Copper Acts Synergistically with Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis

Copper Acts Synergistically with Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis

Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis

In vivo active organometallic-containing antimycotic agents

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