Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China.
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China.
Antimicrob Agents Chemother. 2019 Mar 27;63(4). doi: 10.1128/AAC.01891-18. Print 2019 Apr.
A rapid increase in infection and drug resistance has caused an emergent need for new clinical strategies against this fungal pathogen. In this study, we evaluated the inhibitory activity of a series of 2-alkylaminoquinoline derivatives against isolates. A total of 28 compounds were assessed for their efficacy in inhibiting the yeast-to-hypha transition, which is considered one of the key virulence factors in Several compounds showed strong activity to decrease the morphological transition and virulence of cells. The two leading compounds, compound 1 (2-[piperidin-1-yl]quinolone) and compound 12 (6-methyl-2-[piperidin-1-yl]quinoline), remarkably attenuated hyphal formation and cytotoxicity in a dose-dependent manner, but they showed no toxicity to either cells or human cells. Intriguingly, compound 12 showed an excellent ability to inhibit infection in the mouse oral mucosal infection model. This leading compound also interfered with the expression levels of hypha-specific genes in the cyclic AMP-protein kinase A and mitogen-activated protein kinase signaling pathways. Our findings suggest that 2-alkylaminoquinoline derivatives could potentially be developed as novel therapeutic agents against infection due to their interference with the yeast-to-hypha transition.
感染和耐药性的迅速增加导致人们迫切需要新的临床策略来对抗这种真菌病原体。在这项研究中，我们评估了一系列 2-烷基氨基喹啉衍生物对 分离株的抑制活性。共评估了 28 种化合物抑制酵母向菌丝过渡的功效，这被认为是 几种化合物表现出很强的活性，可以降低 细胞的形态转变和毒力。两种主要化合物，化合物 1（2-[哌啶-1-基]喹啉）和化合物 12（6-甲基-2-[哌啶-1-基]喹啉），以剂量依赖性方式显著减弱了 菌丝形成和细胞毒性，但对 细胞或人细胞均无毒性。有趣的是，化合物 12 显示出在小鼠口腔黏膜感染模型中抑制 感染的出色能力。这种先导化合物还干扰了细胞周期蛋白 AMP-蛋白激酶 A 和丝裂原激活蛋白激酶信号通路中菌丝特异性基因的表达水平。我们的研究结果表明，2-烷基氨基喹啉衍生物可能因其干扰酵母向菌丝过渡而有潜力成为治疗 感染的新型治疗剂。
