Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. República, 2780-157, Oeiras, Portugal.
Division of Molecular Biology/Biocenter, Innsbruck Medical University, Innrain 80-82, 6020, Innsbruck, Austria.
J Biol Inorg Chem. 2020 Dec;25(8):1117-1128. doi: 10.1007/s00775-020-01828-6. Epub 2020 Oct 26.
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.
侵袭性真菌感染（IFIs）是危及生命的，并且由于不良副作用和耐药性的出现，现有的抗真菌药物并不完全有效。唑类药物通常是 IFIs 的治疗选择，越来越多的证据表明铜可以与这些药物协同作用。在这项工作中，我们设计了一种结合唑类和铜（II）结合基团的化合物，并研究了其生物毒性的分子机制。我们的结果表明，化合物 4 及其铜（II）配合物 Cu.4 对念珠菌属均具有活性。我们发现 Cu.4 作为铜（II）载体，导致细胞内活性氧（ROS）的积累，而化合物 4 是一种铁螯合剂，通过降低铁的生物利用度发挥其毒性。有趣的是，虽然 4 对巨噬细胞或 HeLa 细胞的毒性不大，但 Cu.4 显著影响其活力。总的来说，这项工作提供了铜如何与唑类药物结合以扰乱铜稳态的证据，为开发双功能抗真菌药物开辟了新的前景。
