PDF(Pubmed)
Abstract：
Azole resistance in the human fungal pathogen Aspergillus fumigatus is becoming a major threat to global health. To date, mutations in the azole target-encoding cyp51A gene have been implicated in conferring azole resistance, but a steady increase in the number of A. fumigatus isolates with azole resistance resulting from non-cyp51A mutations has been recognized. Previous studies have revealed that some isolates with non-cyp51A mutation-induced azole resistance are related to mitochondrial dysfunction. However, knowledge of the molecular mechanism underlying the involvement of non-cyp51A mutations is limited. In this study, using next-generation sequencing, we found that nine independent azole-resistant isolates without cyp51A mutations had normal mitochondrial membrane potential. Among these isolates, a mutation in a mitochondrial ribosome-binding protein, Mba1, conferred multidrug resistance to azoles, terbinafine, and amphotericin B but not caspofungin. Molecular characterization verified that the TIM44 domain of Mba1 was crucial for drug resistance and that the N terminus of Mba1 played a major role in growth. Deletion of mba1 had no effect on Cyp51A expression but decreased the fungal cellular reactive oxygen species (ROS) content, which contributed to mba1-mediated drug resistance. The findings in this study suggest that some non-cyp51A proteins drive drug resistance mechanisms that result from reduced ROS production induced by antifungals.
摘要：
人类真菌病原体中烟曲霉的唑抗性正在成为全球健康的主要威胁。迄今为止,编码唑类靶标的cyp51A基因中的突变与赋予唑类抗性有关，但是已经认识到由非cyp51A突变导致的具有唑类抗性的烟曲霉分离株的数量稳步增加。先前的研究表明，一些具有非cyp51A突变诱导的唑类耐药的分离株与线粒体功能障碍有关。然而,非cyp51A突变参与的分子机制的知识是有限的.在这项研究中,使用下一代测序，我们发现,无cyp51A突变的9个独立的唑类耐药分离株的线粒体膜电位正常.在这些分离物中,线粒体核糖体结合蛋白的突变,Mba1，赋予了对唑类药物的多药耐药性，特比萘芬,和两性霉素B但不是卡泊芬净.分子表征证实Mba1的TIM44结构域对于耐药性至关重要,并且Mba1的N端在生长中起主要作用。Mba1的缺失对Cyp51A的表达没有影响，但降低了真菌细胞活性氧（ROS）的含量，这导致了mba1介导的耐药性。这项研究的结果表明，一些非cyp51A蛋白驱动抗真菌药物诱导的ROS产生减少导致的耐药机制。
