Suppressed Protein Translation Caused by MSP-8 Deficiency Determines Fungal Multidrug Resistance with Fitness Cost.

IF 14.3 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Mi Zhou, Pengju Yu, Chengcheng Hu, Wenxia Fang, Cheng Jin, Shaojie Li, Xianyun Sun
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Abstract

Antifungal resistance, particularly the rise of multidrug-resistance strains, poses a significant public health threat. In this study, the study identifies a novel multidrug-resistance gene, msp-8, encoding a helicase, through experimental evolution with Neurospora crassa as a model. Deletion of msp-8 conferred multidrug resistance in N. crassa, Aspergillus fumigatus, and Fusarium verticillioides. However, the transcript levels of genes encoding known drug targets or efflux pumps remain unaltered with msp-8 deletion. Interestingly, MSP-8 interacted with ribosomal proteins, and this mutant displays compromised ribosomal function, causing translational disturbance. Notably, inhibition of protein translation enhances resistance to azoles, amphotericin B, and polyoxin B. Furthermore, MSP-8 deficiency or inhibition of translation reduces intracellular ketoconazole accumulation and membrane-bound amphotericin B content, directly causing antifungal resistance. Additionaly, MSP-8 deficiency induces cell wall remodeling, and decreases intracellular ROS levels, further contributing to resistance. The findings reveal a novel multidrug resistance mechanism independent of changes in drug target or efflux pump, while MSP-8 deficiency suppresses protein translation, thereby facilitating the development of resistance with fitness cost. This study provides the first evidence that MSP-8 participates in protein translation and that translation suppression can cause multidrug resistance in fungi, offering new insights into resistance mechanisms in clinical and environmental fungal strains.

抗真菌耐药性,尤其是多重耐药菌株的增加,对公共卫生构成了重大威胁。在这项研究中,研究人员以十字花科黑孢菌(Neurospora crassa)为模型,通过实验进化发现了一种新型多重耐药基因 msp-8,该基因编码一种螺旋酶。缺失 msp-8 基因可使十字花科黑孢菌、烟曲霉和疣孢镰刀菌产生多药抗性。然而,编码已知药物靶标或外排泵的基因的转录水平在缺失 msp-8 后保持不变。有趣的是,MSP-8 与核糖体蛋白相互作用,这种突变体显示出核糖体功能受损,导致翻译紊乱。值得注意的是,抑制蛋白质翻译会增强对唑类、两性霉素 B 和多抗霉素 B 的抗性。此外,MSP-8 缺乏或翻译抑制会减少细胞内酮康唑的积累和膜结合两性霉素 B 的含量,直接导致抗真菌抗性。此外,MSP-8 缺乏还会诱导细胞壁重塑,降低细胞内 ROS 水平,进一步导致抗药性。研究结果揭示了一种新的多药耐药性机制,这种机制与药物靶标或外排泵的变化无关,而 MSP-8 缺乏会抑制蛋白质翻译,从而促进耐药性的产生,并付出健康代价。这项研究首次证明了 MSP-8 参与蛋白质翻译以及翻译抑制可导致真菌产生多药耐药性,为临床和环境真菌菌株的耐药性机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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