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.

Graphic abstract

中文翻译：

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具有离子载体特性的结合铜 (II) 的三唑衍生物对念珠菌属有活性。

摘要

侵袭性真菌感染 (IFI) 会危及生命，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。唑类通常是 IFI 的首选治疗方法，越来越多的证据表明，铜可以与这些药物产生协同作用。在这项工作中，我们设计了一种将唑基和铜 (II) 结合基团结合在一起的化合物，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) 络合物Cu.4对念珠菌属有活性。我们发现Cu.4作为铜 (II) 离子载体，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来发挥其毒性。有趣的是，虽然4对巨噬细胞或 HeLa 细胞的毒性不大，但Cu.4 会显着影响它们的生存能力。总的来说，这项工作提供了铜如何与唑类结合以解除铜稳态的证据，为双功能抗真菌药的开发开辟了新的视野。

图形摘要