Centre for Infectious Diseases and Microbiology, Westmead Millennium Institute and Sydney Emerging Infections and Biosecurity Institute, University of Sydney, Australia.
Mol Pharmacol. 2011 Sep;80(3):476-85. doi: 10.1124/mol.111.072322. Epub 2011 May 24.
Miltefosine has antifungal properties and potential for development as a therapeutic for invasive fungal infections. However, its mode of action in fungi is poorly understood. We demonstrate that miltefosine is rapidly incorporated into yeast, where it penetrates the mitochondrial inner membrane, disrupting mitochondrial membrane potential and leading to an apoptosis-like cell death. COX9, which encodes subunit VIIa of the cytochrome c oxidase (COX) complex in the electron transport chain of the mitochondrial membrane, was identified as a potential target of miltefosine from a genomic library screen of the model yeast Saccharomyces cerevisiae. When overexpressed in S. cerevisiae, COX9, but not COX7 or COX8, led to a miltefosine-resistant phenotype. The effect of miltefosine on COX activity was assessed in cells expressing different levels of COX9. Miltefosine inhibited COX activity in a dose-dependent manner in Cox9p-positive cells. This inhibition most likely contributed to the miltefosine-induced apoptosis-like cell death.
米替福新具有抗真菌特性，并有开发为治疗侵袭性真菌感染的治疗药物的潜力。然而，其在真菌中的作用模式知之甚少。我们证明米替福新可迅速被酵母摄取，穿透线粒体内膜，破坏线粒体膜电位，导致类似细胞凋亡的细胞死亡。细胞色素 c 氧化酶 (COX) 复合物亚基 VIIa 的编码基因 COX9 从模式酵母酿酒酵母的基因组文库筛选中被鉴定为米替福新的潜在靶标。当在酿酒酵母中过表达时，COX9 而不是 COX7 或 COX8 导致米替福新耐药表型。在表达不同水平 COX9 的细胞中评估了米替福新对 COX 活性的影响。米替福新以剂量依赖性方式抑制 Cox9p 阳性细胞中的 COX 活性。这种抑制很可能促成了米替福新诱导的类似细胞凋亡的细胞死亡。
