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bioRxiv · 10.1101/2020.12.28.424579

Growth-mediated negative feedback shapes quantitative antibiotic response

Angermayr, S. A.·Chevereau, G.·Bollenbach, T.
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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 for treatments, 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 only on growth rate, irrespective of its cause. Rewiring the feedback loop alters the dose-response curve in a predictable manner, which we corroborate with a mathematical model. Our results indicate that growth-mediated feedback loops shape drug responses and could be exploited to design evolutionary traps that enable selection against drug resistance.

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Angermayr, S. A., Chevereau, G., Bollenbach, T.. 2020-12-28. Growth-mediated negative feedback shapes quantitative antibiotic response. https://doi.org/10.1101/2020.12.28.424579

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