Analysis scripts and research data for the paper "Mechanisms of drug interactions between translation-inhibiting antibiotics"

Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by "translation bottlenecks": points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of "continuous epistasis" in bacterial physiology.

干扰翻译过程的抗生素在联合使用时，会以多样且难以预测的方式相互作用。在此，我们通过‘翻译瓶颈’来解释这些相互作用：翻译周期中抗生素阻断核糖体进化的关键点。为了阐明翻译抑制剂之间药物相互作用的基本机制，我们通过可诱导控制调节明确翻译周期步骤的翻译因子，遗传性地生成翻译瓶颈。这些扰动精确地模拟了抗生素的作用和药物相互作用，从而支持不同翻译瓶颈之间的相互作用。我们进一步表明，生长规律与药物摄取和结合动力学的结合，能够直接预测大部分观察到的相互作用，但未能预测抑制现象。然而，同时改变两个翻译瓶颈表明，核糖体的高密度流动和翻译因子的竞争解释了之前未被解释的抑制现象。这些结果突出了‘连续上位性’在细菌生理学中的重要性。