Copper-Chelated Hyperbranched Polyethyleneimines with Antifungal Activity against quiescent conidia and germlings of the opportunistic fungal pathogen Aspergillus nidulans

The rising 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. Existing antifungal drugs, although effective, operate via a narrow range of mechanisms, leading to the rapid development of resistance, while they also primarily target growing host cells. Therefore, the need to develop next-generation antifungal agents that function via a broad range of mechanisms and/or to target dormant/quiescent cells is of great importance. In the present study, we investigate the characteristics and the potential antifungal properties of a series of copper-chelated hyperbranched polyethyleneimines (PEI-Cu) of various Cu:primary amino groups of PEI (Cu:N) molar ratios, using the opportunistic pathogen Aspergillus nidulans as a model microorganism. Our results showed that, despite their dissociation, the PEI-Cu¼ and PEI-Cu⅟16 complexes with Cu:N molar ratios of 1:4 and 1:16, respectively, exhibit an apparent fungicidal activity on A. nidulans quiescent conidiospores, while in A. nidulans germlings they affect the hyphal growth rate, produce ROS and alter their mitochondrial morphology network. In addition, no cytotoxic effects were observed on normal human skin fibroblasts at concentrations and 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 against drug-resistant quiescent fungal cells.