Universität zu Köln

Angermayr, S. Andreas ORCID: 0000-0001-8619-2223, Pang, Tin Yau ORCID: 0000-0003-4738-4032, Chevereau, Guillaume, Mitosch, Karin, Lercher, Martin J. and Bollenbach, Tobias ORCID: 0000-0003-4398-476X (2022). Growth-mediated negative feedback shapes quantitative antibiotic response. Mol. Syst. Biol., 18 (9). HOBOKEN: WILEY. ISSN 1744-4292

Full text not available from this repository.

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Angermayr, S. Andreas UNSPECIFIED orcid.org/0000-0001-8619-2223 UNSPECIFIED Pang, Tin Yau UNSPECIFIED orcid.org/0000-0003-4738-4032 UNSPECIFIED Chevereau, Guillaume UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitosch, Karin UNSPECIFIED UNSPECIFIED UNSPECIFIED Lercher, Martin J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bollenbach, Tobias UNSPECIFIED orcid.org/0000-0003-4398-476X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-688633
DOI:	10.15252/msb.202110490
Journal or Publication Title:	Mol. Syst. Biol.
Volume:	18
Number:	9
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1744-4292
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ESCHERICHIA-COLI; GENE-EXPRESSION; DIHYDROFOLATE-REDUCTASE; RESISTANCE; REPORTERS; MUTATIONS; EVOLUTION; BACTERIA; LIBRARY; STRESS Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68863