Abstract
A gradual rise in immunocompromised patients over past years has led to the increasing incidence of invasive fungal infections. Development of effective fungicides can not only provide new means for clinical treatment, but also reduce the occurrence of fungal resistance. We identified a new antifungal agent (4-phenyl-1, 3-thiazol-2-yl), hydrazine (numbered as 31C) which showed high-efficiency, broad-spectrum and specific activities. The minimum inhibitory concentration of 31C against pathogenic fungi was between 0.0625-4 μg/ml in vitro, while 31C had no obvious cytotoxicity to human umbilical vein endothelial cells with the concentration of 4 μg/ml. In addition, 31C of 0.5 μg/ml could exhibit significant fungicidal activity and inhibit the biofilm formation of C. albicans. In vivo fungal infection model showed that 31C of 10 mg/kg significantly increased the survival rate of Galleria mellonella. Further study revealed that 31C-treatment increased the reactive oxygen species (ROS) in C. albicans and elevated the expression of some genes related to anti-oxidative stress response, including CAP1, CTA1, TRR1, and SODs. Consistently, 31C-induced high levels of intracellular ROS resulted in considerable DNA damage, which played a critical role in antifungal-induced cellular death. The addition of ROS scavengers, such as glutathione (GSH), N-Acetyl-L-cysteine (NAC) or oligomeric proanthocyanidins (OPC), dramatically reduced the antifungal activities of 31C and rescued the 31C-induced filamentation defect. Collectively, these results showed that 31C exhibited strong antifungal activity and induced obvious oxidative damage, which indicated that compounds with a structure similar to 31C may provide new sight for antifungal drug development.
Highlights
In recent years, the usage of immunosuppressive agents and the increasing numbers of immunodeficiency patients and severe infections has led to growing incidence of fungal infections (Pappas et al, 2018)
We have synthesized many compounds with different scaffolds and screened antifungal activities by liquid micro-dilution method. (4-phenyl-1, 3-thiazol-2-yl) hydrazine, which is similar to the structure of EM-01D2 referred by Logu etal, exhibits high in vitro antifungal activities against pathogenic fungi such as Candida, Aspergillus, Cryptococcus, and Dermatophytes
During the process of preliminary screening, we found that the minimum inhibitory concentration (MIC) of 31C against C. albicans SC5314 was 0.0625 μg/ml
Summary
The usage of immunosuppressive agents and the increasing numbers of immunodeficiency patients and severe infections has led to growing incidence of fungal infections (Pappas et al, 2018). The limitations of fungal diagnosis and antifungal drugs result in the high mortality rate of systemic fungal infection as 20–50% (Kullberg and Arendrup, 2015; Papon et al, 2020). The development of broadspectrum drugs with new antifungal mechanisms is an urgent request for treating fungal infections. They referred a guideline for the ideal antifungal agent, which should have fungicidal activity, a broad spectrum and good selectivity toward a fungal-specific target (Liu et al, 2016). Powerful fungicides can effectively prevent the development of antifungal resistance. Finding specific fungicidal leading compounds is an essential task for the development of ideal antifungal drugs (Perlin et al, 2017)
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