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A copper(II)-binding triazole derivative with ionophore properties is active against Candida spp.

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A Correction to this article was published on 29 May 2021

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Abstract

Invasive fungal infections (IFIs) are life threatening and existing antifungal drugs are not completely effective due to undesirable side effects and resistance emergence. Azoles are often the treatment of choice for IFIs and growing evidence suggests that copper can act synergistically with these drugs. In this work, we designed a compound bringing together azole and copper(II)-binding groups and studied the molecular mechanisms underlying its biological toxicity. Our results show that both the compound, 4, and its copper(II) complex, Cu.4, are active against Candida spp. We found that Cu.4 acts as a copper(II) ionophore, which results in the intracellular accumulation of reactive oxygen species (ROS), whereas compound 4 is an iron chelator and exerts its toxicity by decreasing iron bioavailability. Interestingly, while 4 is not very toxic to macrophages or HeLa cells, Cu.4 significantly affects their viability. Overall, this work provides evidence of how copper can be combined with azoles to deregulate copper homeostasis, opening new horizons for the development of bifunctional antifungals.

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Acknowledgements

This work was supported by (i) Project LISBOA-01-0145-FEDER-007660 (“Microbiologia Molecular, Estrutural e Celular”) funded by FEDER funds through COMPETE2020—“Programa Operacional Competitividade e Internacionalização” (POCI); (ii) “Fundação para a Ciência e a Tecnologia” (FCT) through programme IF (IF/00124/2015) to C.P.; (iii) the European Union’s Horizon 2020 research and innovation programme under grant agreement No 810856; (iv) COST Action CA15133, supported by COST (European Cooperation in Science and Technology), (v) PPBI—Portuguese Platform of BioImaging (PPBI-POCI-01-0145-FEDER-022122) co-funded by national funds from OE—“Orçamento de Estado” and by FEDER. A.G.C. was supported by a FCT PhD fellowship (SFRH/BD/118866/2016), and (vi) Austrian Science Fund (FWF) doctoral program “host response in opportunistic infections (HOROS, W1253 to HH)”. We are grateful to Ling Lu (Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, China) for providing the A. fumigatus crpA mutant strain. We thank Cristina Leitão (Research Facilities ITQB NOVA) for technical assistance in HPLC.

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Authors and Affiliations

  1. Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. República, 2780-157, Oeiras, Portugal

    A. Gaspar-Cordeiro, S. da Silva, C. Rodrigues-Pousada, L. M. P. Lima & C. Pimentel

  2. Division of Molecular Biology/Biocenter, Innsbruck Medical University, Innrain 80-82, 6020, Innsbruck, Austria

    M. Aguiar & H. Haas

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  1. A. Gaspar-Cordeiro
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Gaspar-Cordeiro, A., da Silva, S., Aguiar, M. et al. A copper(II)-binding triazole derivative with ionophore properties is active against Candida spp.. J Biol Inorg Chem 25, 1117–1128 (2020). https://doi.org/10.1007/s00775-020-01828-6

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