EFFECTS OF BENZIMIDAZOLE FUNGICIDES ON GENE TRANSCRIPTION IN YEAST

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。最近在监测基因活性的激活和抑制能力（“基因芯片”技术）方面取得的进展，开启了在对基因转录的整体影响水平上研究药物活性的可能性，而不是在对分离蛋白质的活性水平上。这种类型的监测有可能揭示有关耐药性机制和活动方式的重要信息，否则这些信息是无法获得的。作为开发这类方法的试验台，我们选择了探索苯并咪唑类杀菌剂对酿酒酵母基因表达模式的构效关系。我们通过合成这些杀菌剂的位置索引文库，处理酵母，并将基因活性模式与初级药物结构相关联来接近该项目。对这些文库成员（通常为200 - 300 MW）的结构和纯度进行表征的一种特别简便的方法是EI质谱的碎片分析。当与气相色谱相结合时，这种方法有可能提供关于单个库成员的纯度及其身份的信息。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent advances in the ability to monitor activation and repression of gene activity ("gene chip" technology) have opened the possibility of studying the activity of drugs at the level of global effects upon gene transcription rather than the level of activity against isolated proteins. This type of monitoring has the potential to reveal important information about drug resistance mechanisms and modes of activity that are otherwise unavailable. As a test-bed for developing such methods, we have chosen to explore the structure activity relationship of the benzimidazole fungicides towards the gene expression patterns of brewer's yeast (S. cerevisiae). We have approached the project by synthesizing a position-indexed library of these fungicides, treating yeast, and correlating the patterns of gene activity with primary drug structure. One particularly facile method for characterization of the structure and purity of these library members (generally of 200 - 300 MW) is by fragmentation analysis from EI mass spectrometry. When coupled with gas chromatography, this approach has the potential to provide information about both the purity of individual library members and their identity.