Department of Pediatrics, University of California, San Diego, Gilman Dr, La Jolla, CA, 92093, USA.
Department of Biological Sciences, University of Pittsburgh, 4249 Fifth Avenue, Pittsburgh, PA, 15260, USA.
Commun Biol. 2022 Feb 11;5(1):128. doi: 10.1038/s42003-022-03076-7.
In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in Saccharomyces cerevisiae. Sequence analysis identified many genes contributing to the resistance phenotype as well as numerous amino acids in potential targets that may play a role in compound binding. Our work shows that compound-target pairs can be conserved across multiple species. The set of 25 most frequently mutated genes was enriched for transcription factors, and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function SNVs found in a 170 amino acid domain in the two ZnC transcription factors YRR1 and YRM1 (p < 1 × 10). This remarkable enrichment for transcription factors as drug resistance genes highlights their important role in the evolution of antifungal xenobiotic resistance and underscores the challenge to develop antifungal treatments that maintain potency.
通过体外进化和全基因组分析，全面鉴定了酿酒酵母中化学抗性的遗传决定因素。序列分析确定了许多与耐药表型相关的基因，以及许多可能在化合物结合中发挥作用的潜在靶标中的氨基酸。我们的工作表明，化合物-靶标对可以在多个物种中保守。最常突变的 25 个基因集富集了转录因子，对于近 25%的化合物，耐药性是由在两个 ZnC 转录因子 YRR1 和 YRM1 中 170 个氨基酸域中发现的 100 个独立衍生的功能获得性 SNVs 之一介导的（p<1×10）。作为耐药基因的转录因子的这种显著富集突出了它们在抗真菌异生物质耐药性进化中的重要作用，并强调了开发保持效力的抗真菌治疗方法所面临的挑战。
