Institute for Biological Physics, University of Cologne, Cologne, Germany.
Institute of Science and Technology Austria, Klosterneuburg, Austria.
Mol Syst Biol. 2022 Sep;18(9):e10490. doi: 10.15252/msb.202110490.
Dose-response relationships are a general concept for quantitatively describing biological systems across multiple scales, from the molecular to the whole-cell level. A clinically relevant example is the bacterial growth response to antibiotics, which is routinely characterized by dose-response curves. The shape of the dose-response curve varies drastically between antibiotics and plays a key role in treatment, drug interactions, and resistance evolution. However, the mechanisms shaping the dose-response curve remain largely unclear. Here, we show in Escherichia coli that the distinctively shallow dose-response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that this upregulation is not a specific response to trimethoprim but follows a universal trend line that depends primarily on the growth rate, irrespective of its cause. Rewiring the feedback loop alters the dose-response curve in a predictable manner, which we corroborate using a mathematical model of cellular resource allocation and growth. Our results indicate that growth-mediated feedback loops may shape drug responses more generally and could be exploited to design evolutionary traps that enable selection against drug resistance.
剂量反应关系是一个通用概念，用于定量描述从分子到全细胞水平的多个尺度上的生物系统。一个与临床相关的例子是抗生素对细菌生长的反应，其通常通过剂量反应曲线来表征。抗生素之间的剂量反应曲线的形状差异很大，在治疗、药物相互作用和耐药性进化中起着关键作用。然而，塑造剂量反应曲线的机制在很大程度上仍不清楚。在这里，我们在大肠杆菌中表明，抗生素甲氧苄啶（trimethoprim）独特的浅剂量反应曲线是由负生长介导的反馈环引起的：甲氧苄啶减缓生长，进而削弱了这种抗生素的作用。在分子水平上，这种反馈是由药物靶标二氢叶酸还原酶（FolA/DHFR）的上调引起的。我们表明，这种上调不是对甲氧苄啶的特定反应，而是遵循一条主要取决于生长速率的通用趋势线，而与生长速率的原因无关。重新布线反馈环以可预测的方式改变剂量反应曲线，我们使用细胞资源分配和生长的数学模型来验证这一点。我们的结果表明，生长介导的反馈环可能更普遍地塑造药物反应，并可用于设计进化陷阱，以选择对抗耐药性。
