Fungal growth-dependent gene coregulation is strongly implicated in alteration of gene-encoding target proteases ruling with an antifungal resistance niche and biology of resistant mutants. On the basis of multi-alterative processes in this platform, the resistance-modifying strategy is designed in ketoconazole resistant Candida albicans and evaluated with less selective Momordica charantia protein and allosterically phosphorylated derivatives at the Thr102, Thr24 and Thr255 sites, respectively. We demonstrate absolutely chemo-sensitizing efficacy regarding stepwise-modifying resistance in sensitivity, by a load of only 26.23–40.00 μg/l agents in Sabouraud's dextrose broth. Five successive modifying-steps realize the decreasing of ketoconazole E-test MIC50 from 11.10 to a lower level than 0.10 mg/l. With the ketoconazole resistance-modifying, colony undergoes a high-frequency morphological switch between high ploidy (opaque) and small budding haploid (white). A cellular event in the first modifying-step associates with relatively slow exponential growth (ie, a 4-h delay)-dependent action, mediated by agents adsorption. Moreover, multiple molecular roles are coupled with intracellularly and extracellularly binding to ATP-dependent RNA helicase dbp6; the 0.08–2.45 fold upregulation of TATA-box-binding protein, rRNA-processing protein and translation initiation factor 5A; and the 7.52–55.33% decrease of cytochrome P450 lanosterol 14α-demethylase, glucan 1, 3-β glucosidase, candidapepsin-1 and 1-acylglycerol-3-phosphate O-acyltransferase. Spatial and temporal gene coregulation, in the transcription and translation initiation stages with rRNA-processing, is a new coprocessing platform enabling target protease attenuations for resistance-impairing. An updated resistance-modifying measure of these agents in the low-dose antifungal strategic design may provide opportunities to a virtually safe therapy that is in high dose-dependency.

中文翻译：

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苦瓜蛋白和磷酸化衍生物基于白色念珠菌生长依赖性基因共调节的抗真菌抗性修饰多重作用。


真菌生长依赖性基因共调节与基因编码靶蛋白酶的改变密切相关，这些蛋白酶决定抗真菌耐药性生态位和耐药突变体的生物学。基于该平台中的多替代过程，在酮康唑耐药白色念珠菌中设计了耐药性修饰策略，并分别用选择性较低的苦瓜蛋白和 Thr102、Thr24 和 Thr255 位点的变构磷酸化衍生物进行评估。我们通过在沙氏葡萄糖肉汤中添加仅 26.23–40.00 μg/l 的试剂，证明了在逐步改变敏感性耐药性方面的绝对化学增敏功效。五个连续的修饰步骤实现了酮康唑E-test MIC50从11.10降低到低于0.10 mg/l的水平。通过酮康唑抗性修饰，菌落在高倍性（不透明）和小出芽单倍体（白色）之间经历高频形态转换。第一个修饰步骤中的细胞事件与相对缓慢的指数生长（即，4小时延迟）依赖性作用相关，由试剂吸附介导。此外，多种分子作用与细胞内和细胞外与 ATP 依赖性 RNA 解旋酶 dbp6 的结合相结合； TATA-box结合蛋白、rRNA加工蛋白和翻译起始因子5A上调0.08-2.45倍；细胞色素 P450 羊毛甾醇 14α-去甲基酶、葡聚糖 1, 3-β 葡萄糖苷酶、念珠菌蛋白酶-1 和 1-酰基甘油-3-磷酸 O-酰基转移酶减少 7.52–55.33%。 在 rRNA 处理的转录和翻译起始阶段，空间和时间基因共调节是一种新的共处理平台，能够减弱目标蛋白酶的抗性损伤。在低剂量抗真菌策略设计中对这些药物进行更新的耐药性修改措施可能会为高度剂量依赖性的几乎安全的治疗提供机会。