Growth‐mediated negative feedback shapes quantitative antibiotic response

Abstract

Abstract 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.

Keywords

• antibiotics
• dihydrofolate reductase (DHFR)
• dose–response curve
• feedback loops
• resource allocation model