A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans.
A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans.
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一种新型抗真菌剂（4-苯基-1, 3-噻唑-2-基）肼可诱导白色念珠菌氧化损伤。
DOI：
10.3389/fcimb.2020.578956
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发表时间：
2020
影响因子：
5.7
通讯作者：
Jiang YY
中科院分区：
文献类型：
--
作者：
Lv QZ;Ni TJ;Li LP;Li T;Zhang DZ;Jiang YY
过去几年，免疫功能低下患者的逐渐增加导致侵袭性真菌感染的发病率不断增加。开发有效的杀菌剂不仅可以为临床治疗提供新的手段，而且可以减少真菌耐药性的发生。我们发现了一种新的抗真菌剂（4-苯基-1, 3-噻唑-2-基）肼（编号为31C），它表现出高效、广谱和特异的活性。 31C体外对病原真菌的最低抑制浓度在0.0625-4μg/ml之间，而4μg/ml浓度的31C对人脐静脉内皮细胞无明显细胞毒性。此外，0.5μg/ml的31C可表现出显着的杀菌活性并抑制白色念珠菌生物膜的形成。体内真菌感染模型显示，10mg/kg的31C显着提高大蜡螟的存活率。进一步的研究表明，31C处理增加了白色念珠菌中的活性氧（ROS），并提高了一些与抗氧化应激反应相关的基因的表达，包括CAP1、CTA1、TRR1和SOD。一致地，31C诱导的高水平细胞内ROS导致相当大的DNA损伤，这在抗真菌诱导的细胞死亡中发挥了关键作用。添加 ROS 清除剂，如谷胱甘肽 (GSH)、N-乙酰-L-半胱氨酸 (NAC) 或低聚原花青素 (OPC)，可显着降低 31C 的抗真菌活性，并挽救 31C 诱导的丝状形成缺陷。总的来说，这些结果表明31C表现出很强的抗真菌活性并诱导明显的氧化损伤，这表明与31C结构相似的化合物可能为抗真菌药物的开发提供新的思路。
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.