Farha Maya A, Brown Eric D
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Chem Biol. 2010 Aug 27;17(8):852-62. doi: 10.1016/j.chembiol.2010.06.008.
While cell-based screens have considerable power in identifying new chemical probes of biological systems and leads for new drugs, a major challenge to the utility of such compounds is in connecting phenotype with a cellular target. Here, we present a systematic study to elucidate the mechanism of action of uncharacterized inhibitors of the growth of Escherichia coli through careful analyses of interactions with compounds of known biological activity. We studied growth inhibition with a collection of 200 antibacterial compounds when systematically combined with a panel of 14 known antibiotics of diverse mechanism and chemical class. Our work revealed a high frequency of synergistic chemical-chemical interactions where the interaction profiles were unique to the various compound pairs. Thus, the work revealed that chemical-chemical interaction data provides a fingerprint of biological activity and testable hypotheses regarding the mechanism of action of the novel bioactive molecules. In the study reported here, we determined the mode of action of an inhibitor of folate biosynthesis and a DNA gyrase inhibitor. Moreover, we identified eight membrane-active compounds, found to be promiscuously synergistic with known bioactives.
虽然基于细胞的筛选在识别生物系统的新化学探针和新药先导物方面具有相当大的作用，但此类化合物实用性的一个主要挑战在于将表型与细胞靶点联系起来。在此，我们通过仔细分析与已知生物活性化合物的相互作用，开展了一项系统性研究，以阐明未表征的大肠杆菌生长抑制剂的作用机制。当将一组200种抗菌化合物与一组14种已知的、作用机制和化学类别各异的抗生素系统地联合使用时，我们研究了其对生长的抑制作用。我们的工作揭示了高频的化学 - 化学协同相互作用，其中相互作用谱对于各种化合物对而言是独特的。因此，这项工作表明化学 - 化学相互作用数据提供了生物活性的指纹以及关于新型生物活性分子作用机制的可测试假设。在本文报道的研究中，我们确定了一种叶酸生物合成抑制剂和一种DNA促旋酶抑制剂的作用模式。此外，我们鉴定出了八种膜活性化合物，发现它们与已知生物活性物质普遍存在协同作用。
