Tsiourvas Dimitris, Sideratou Zili, Mavrogonatou Eleni, Kletsas Dimitris, Sophianopoulou Vicky, Gerostathis Spiros
Institute of Nanoscience and Nanotechnology, National Centre for Scientific Research "Demokritos", Agia Paraskevi, 15341, Greece.
Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications (IBA), National Centre for Scientific Research "Demokritos", Agia Paraskevi, 15341, Greece.
Sci Rep. 2025 Jul 16;15(1):25711. doi: 10.1038/s41598-025-11018-6.
The increase in the number of immunocompromised individuals combined with the severity of fungal infections in the general population has contributed to a significant increase in opportunistic fungal infections, which are often associated with high mortality rates. Although effective, existing antifungal drugs operate via a narrow range of mechanisms, leading to the rapid development of resistance and they primarily target growing host cells. Therefore, the need to develop next-generation antifungal agents that function via a broad range of mechanisms and/or target dormant/quiescent cells is highly important. In the present study, we investigated the characteristics and potential antifungal properties of a series of copper-chelated hyperbranched polyethyleneimines (PEI-Cu) with various molar ratios of Cu:primary amino groups of PEI (Cu: N), using the opportunistic pathogen Aspergillus nidulans as a model microorganism. Our results showed that PEI-Cu¼ and PEI-Cu¹⁄₁₆ complexes with Cu: N molar ratios of 1:4 and 1:16, respectively, retain the fungicidal activity of PEI. Cu chelation seemed to delay the internalization of PEI-Cu, but they were found to exhibit apparent fungicidal activity on A. nidulans quiescent conidiospores while they affected hyphal growth rate, redox status and mitochondrial network morphology in A. nidulans germlings. In addition, no cytotoxic effects were observed on normal human skin fibroblasts at concentrations or incubation times that were entirely inhibitory for A. nidulans. Overall, our results suggest that the investigated PEI-Cu complexes are promising antifungals, and their underlying mechanism of action deserves further investigation, especially for use against drug-resistant quiescent fungal cells.
免疫功能低下个体数量的增加，再加上普通人群中真菌感染的严重性，导致机会性真菌感染显著增加，而这些感染往往与高死亡率相关。尽管现有抗真菌药物有效，但它们通过有限的几种机制发挥作用，导致耐药性迅速发展，并且它们主要针对生长中的宿主细胞。因此，开发通过多种机制发挥作用和/或靶向休眠/静止细胞的下一代抗真菌药物非常重要。在本研究中，我们以机会性病原体构巢曲霉作为模式微生物，研究了一系列具有不同铜与聚乙烯亚胺（PEI）伯氨基摩尔比（Cu:N）的铜螯合超支化聚乙烯亚胺（PEI-Cu）的特性和潜在抗真菌特性。我们的结果表明，Cu:N摩尔比分别为1:4和1:16的PEI-Cu¼和PEI-Cu¹⁄₁₆复合物保留了PEI的杀菌活性。铜螯合似乎延迟了PEI-Cu的内化，但发现它们对构巢曲霉静止分生孢子具有明显的杀菌活性，同时它们影响构巢曲霉芽管的菌丝生长速率、氧化还原状态和线粒体网络形态。此外，在对构巢曲霉完全具有抑制作用的浓度或孵育时间下，未观察到对正常人皮肤成纤维细胞的细胞毒性作用。总体而言，我们的结果表明，所研究的PEI-Cu复合物是有前景的抗真菌剂，其潜在的作用机制值得进一步研究，特别是用于对抗耐药性静止真菌细胞。
