Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis
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 ye...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.920574/full |
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| author | Ana Gaspar-Cordeiro Catarina Amaral Vânia Pobre Wilson Antunes Wilson Antunes Ana Petronilho Paulo Paixão Paulo Paixão António P. Matos Catarina Pimentel |
| author_facet | Ana Gaspar-Cordeiro Catarina Amaral Vânia Pobre Wilson Antunes Wilson Antunes Ana Petronilho Paulo Paixão Paulo Paixão António P. Matos Catarina Pimentel |
| author_sort | Ana Gaspar-Cordeiro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T07:43:54Z |
| format | Article |
| id | doaj.art-7a210609591948a5a519a6373115f032 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-12T07:43:54Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-7a210609591948a5a519a6373115f0322022-12-22T00:32:42ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-06-011310.3389/fmicb.2022.920574920574Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc HomeostasisAna Gaspar-Cordeiro0Catarina Amaral1Vânia Pobre2Wilson Antunes3Wilson Antunes4Ana Petronilho5Paulo Paixão6Paulo Paixão7António P. Matos8Catarina Pimentel9Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, PortugalCentro de Investigação da Academia Militar (CINAMIL), Unidade Militar Laboratorial de Defesa Biológica e Química (UMLDBQ), Lisbon, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, PortugalUnidade de Infeção, Faculdade de Ciências Médicas, Chronic Diseases Research Centre – CEDOC, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, PortugalLaboratório de Patologia Clínica – SYNLAB, Hospital da Luz, Lisbon, PortugalEgas Moniz Interdisciplinary Research Centre, Egas Moniz Higher Education Cooperative, Caparica, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, PortugalThe 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.https://www.frontiersin.org/articles/10.3389/fmicb.2022.920574/fullcopperyeastantifungalstress responseCandidazap1 |
| spellingShingle | Ana Gaspar-Cordeiro Catarina Amaral Vânia Pobre Wilson Antunes Wilson Antunes Ana Petronilho Paulo Paixão Paulo Paixão António P. Matos Catarina Pimentel Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis Frontiers in Microbiology copper yeast antifungal stress response Candida zap1 |
| title | Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis |
| title_full | Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis |
| title_fullStr | Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis |
| title_full_unstemmed | Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis |
| title_short | Copper Acts Synergistically With Fluconazole in Candida glabrata by Compromising Drug Efflux, Sterol Metabolism, and Zinc Homeostasis |
| title_sort | copper acts synergistically with fluconazole in candida glabrata by compromising drug efflux sterol metabolism and zinc homeostasis |
| topic | copper yeast antifungal stress response Candida zap1 |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.920574/full |
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