Lv Quanzhen, Yan Lan, Wang Jinxin, Feng Jia, Gao Lu, Qiu Lijuan, Chao Wen, Qin Yu-Lin, Jiang Yuanying
School of Pharmacy, Naval Medical University, Shanghai, People's Republic of China.
Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
Microbiol Spectr. 2023 Feb 15;11(2):e0320922. doi: 10.1128/spectrum.03209-22.
Based on the structural modification of SM21, xy12, a new pyrylium salt derivative with enhanced antifungal activities, was synthesized. The MICs (MIC) of xy12 against Candida albicans ranged from 0.125 to 0.25 μg/mL, about 2-fold lower than those of SM21. In addition, xy12 inhibited hypha and biofilm formation in C. albicans in a dose-dependent manner. A total of 3,454 differentially expressed genes and 260 differential metabolites were identified in the xy12-treated C. albicans by RNA-seq and non-targeted metabolomics. By integrating KEGG pathway enrichment analysis, we found that inhibition of oxidative phosphorylation was the important antifungal mechanism of action of xy12. Electron transport through mitochondrial respiratory complexes I to IV is the common process of oxidative phosphorylation. Compared with the sensitivity of the wild-type SC5314 to xy12, decreased sensitivities in mitochondrial complex I (CI)-deficient mutants and increased sensitivities in mitochondrial complex III- and IV-deficient mutants suggested that the antifungal effects of xy12 were dependent on CI. Consistently, xy12 exhibited antagonism with rotenone, an inhibitor of CI, and significantly inhibited the expression and activity of CI. Meanwhile, the phenotypes in the xy12-treated C. albicans were similar to those in the CI-deficient mutants, such as decreased ATP production, reduced mitochondrial membrane potential, loss of mitochondrial DNA, inability to utilize nonfermentative carbon sources, and decreased cell wall N-linked mannoproteins. Collectively, our results revealed that the pyrylium salt xy12 could constrain oxidative phosphorylation by inhibiting mitochondrial complex I in C. albicans, providing a novel lead compound for the development of mitochondria-targeted antifungal drugs. The development of new antifungal drugs is critical for solving the problem of antifungal resistance and expanding the limited variety of clinical antifungal drugs. Based on the modification of the pyrylium salt SM21, a new lead compound, xy12, was synthesized which was effective against species both and . In this study, conjoined analysis of the transcriptome and metabolome elucidated the antifungal mechanism of action of xy12, which inhibited the activity of mitochondrial complex I in C. albicans. Targeting fungi-specific mitochondrial complex proteins has been reported as a promising antifungal strategy. Our study provided a new lead compound for targeting C. albicans mitochondrial complex I, which could be beneficial for discovering novel antifungal drugs.
基于SM21的结构修饰，合成了一种具有增强抗真菌活性的新型吡喃盐衍生物xy12。xy12对白色念珠菌的最低抑菌浓度（MIC）范围为0.125至0.25μg/mL，比SM21的MIC低约2倍。此外，xy12以剂量依赖性方式抑制白色念珠菌的菌丝和生物膜形成。通过RNA测序和非靶向代谢组学在经xy12处理的白色念珠菌中总共鉴定出3454个差异表达基因和260种差异代谢物。通过整合KEGG通路富集分析，我们发现抑制氧化磷酸化是xy12重要的抗真菌作用机制。通过线粒体呼吸复合物I至IV的电子传递是氧化磷酸化的常见过程。与野生型SC5314对xy12的敏感性相比，线粒体复合物I（CI）缺陷型突变体的敏感性降低，而线粒体复合物III和IV缺陷型突变体的敏感性增加，这表明xy12的抗真菌作用依赖于CI。一致地，xy12与CI抑制剂鱼藤酮表现出拮抗作用，并显著抑制CI的表达和活性。同时，经xy12处理的白色念珠菌中的表型与CI缺陷型突变体中的表型相似，如ATP产生减少、线粒体膜电位降低、线粒体DNA丢失、无法利用非发酵碳源以及细胞壁N-连接甘露糖蛋白减少。总体而言，我们的结果表明，吡喃盐xy12可通过抑制白色念珠菌中的线粒体复合物I来抑制氧化磷酸化，为开发线粒体靶向抗真菌药物提供了一种新型先导化合物。开发新型抗真菌药物对于解决抗真菌耐药性问题和扩大临床抗真菌药物种类有限的局面至关重要。基于吡喃盐SM21的修饰，合成了一种新型先导化合物xy12，它对[此处原文缺失相关物种信息]均有效。在本研究中，转录组和代谢组的联合分析阐明了xy12的抗真菌作用机制，即它抑制白色念珠菌中线粒体复合物I的活性。靶向真菌特异性线粒体复合物蛋白已被报道为一种有前景的抗真菌策略。我们的研究为靶向白色念珠菌线粒体复合物I提供了一种新型先导化合物，这可能有助于发现新型抗真菌药物。
