Qi Qin, Angermayr S Andreas, Bollenbach Tobias
Institute of Science and Technology Austria, Klosterneuburg, Austria.
Institute for Biological Physics, University of Cologne, Cologne, Germany.
Front Microbiol. 2021 Oct 20;12:760017. doi: 10.3389/fmicb.2021.760017. eCollection 2021.
Understanding interactions between antibiotics used in combination is an important theme in microbiology. Using the interactions between the antifolate drug trimethoprim and the ribosome-targeting antibiotic erythromycin in as a model, we applied a transcriptomic approach for dissecting interactions between two antibiotics with different modes of action. When trimethoprim and erythromycin were combined, the transcriptional response of genes from the sulfate reduction pathway deviated from the dominant effect of trimethoprim on the transcriptome. We successfully altered the drug interaction from additivity to suppression by increasing the sulfate level in the growth environment and identified sulfate reduction as an important metabolic determinant that shapes the interaction between the two drugs. Our work highlights the potential of using prioritization of gene expression patterns as a tool for identifying key metabolic determinants that shape drug-drug interactions. We further demonstrated that the sigma factor-binding protein gene shapes the interactions between the two antibiotics, which provides a rare example of how naturally occurring variations between strains of the same bacterial species can sometimes generate very different drug interactions.
了解联合使用的抗生素之间的相互作用是微生物学中的一个重要主题。以抗叶酸药物甲氧苄啶与靶向核糖体的抗生素红霉素之间的相互作用为例，我们应用转录组学方法剖析两种作用方式不同的抗生素之间的相互作用。当甲氧苄啶和红霉素联合使用时，硫酸盐还原途径基因的转录反应偏离了甲氧苄啶对转录组的主要影响。通过提高生长环境中的硫酸盐水平，我们成功地将药物相互作用从相加作用改变为抑制作用，并确定硫酸盐还原是塑造这两种药物相互作用的重要代谢决定因素。我们的工作突出了将基因表达模式的优先级排序作为识别塑造药物 - 药物相互作用的关键代谢决定因素的工具的潜力。我们进一步证明，sigma因子结合蛋白基因塑造了这两种抗生素之间的相互作用，这提供了一个罕见的例子，说明同一细菌物种不同菌株之间的自然发生变异有时会产生非常不同的药物相互作用。
