Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5, Kashiwa-no-ha, Kashiwa City, Chiba, 277-8561, Japan.
Sci Rep. 2024 Aug 6;14(1):17093. doi: 10.1038/s41598-024-67634-1.
Terbinafine, fluconazole, and amorolfine inhibit fungal ergosterol synthesis by acting on their target enzymes at different steps in the synthetic pathway, causing the accumulation of various intermediates. We found that the effects of these three in- hibitors on yeast morphology were different. The number of morphological parameters commonly altered by these drugs was only approximately 6% of the total. Using a rational strategy to find commonly changed parameters,we focused on hidden essential similarities in the phenotypes possibly due to decreased ergosterol levels. This resulted in higher apparent morphological similarity. Improvements in morphological similarity were observed even when canonical correlation analysis was used to select biologically meaningful morphological parameters related to gene function. In addition to changes in cell morphology, we also observed differences in the synergistic effects among the three inhibitors and in their fungicidal effects against pathogenic fungi possibly due to the accumulation of different intermediates. This study provided a comprehensive understanding of the properties of inhibitors acting in the same biosynthetic pathway.
特比萘芬、氟康唑和阿莫罗芬通过在合成途径的不同步骤作用于靶酶来抑制真菌麦角固醇合成，导致各种中间产物的积累。我们发现这三种抑制剂对酵母形态的影响不同。这些药物共同改变的形态参数数量仅约为总数的 6%。通过使用合理的策略找到共同改变的参数，我们专注于由于麦角固醇水平降低而可能导致的隐藏的基本表型相似性。这导致了更高的明显形态相似性。即使使用典型相关分析选择与基因功能相关的有生物学意义的形态参数，也观察到形态相似性的改善。除了细胞形态的变化外，我们还观察到三种抑制剂之间的协同作用以及它们对致病性真菌的杀菌作用的差异，这可能是由于不同中间产物的积累所致。这项研究提供了对作用于同一生物合成途径的抑制剂特性的全面了解。
