Universität zu Köln

Pinheiro, Fernanda ORCID: 0000-0002-0132-0562, Warsi, Omar ORCID: 0000-0003-3175-1184, Andersson, Dan I. and Laessig, Michael (2021). Metabolic fitness landscapes predict the evolution of antibiotic resistance. Nat. Ecol. Evol., 5 (5). S. 677 - 696. BERLIN: NATURE PORTFOLIO. ISSN 2397-334X

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Abstract

This study develops metabolic fitness models that integrate drug action with evolutionary response to predict growth rates of resistance mutations and prevalent mechanisms of antibiotic resistance in Escherichia coli. Bacteria evolve resistance to antibiotics by a multitude of mechanisms. A central, yet unsolved question is how resistance evolution affects cell growth at different drug levels. Here, we develop a fitness model that predicts growth rates of common resistance mutants from their effects on cell metabolism. The model maps metabolic effects of resistance mutations in drug-free environments and under drug challenge; the resulting fitness trade-off defines a Pareto surface of resistance evolution. We predict evolutionary trajectories of growth rates and resistance levels, which characterize Pareto resistance mutations emerging at different drug dosages. We also predict the prevalent resistance mechanism depending on drug and nutrient levels: low-dosage drug defence is mounted by regulation, evolution of distinct metabolic sectors sets in at successive threshold dosages. Evolutionary resistance mechanisms include membrane permeability changes and drug target mutations. These predictions are confirmed by empirical growth inhibition curves and genomic data of Escherichia coli populations. Our results show that resistance evolution, by coupling major metabolic pathways, is strongly intertwined with systems biology and ecology of microbial populations.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pinheiro, Fernanda UNSPECIFIED orcid.org/0000-0002-0132-0562 UNSPECIFIED Warsi, Omar UNSPECIFIED orcid.org/0000-0003-3175-1184 UNSPECIFIED Andersson, Dan I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Laessig, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-575056
DOI:	10.1038/s41559-021-01397-0
Journal or Publication Title:	Nat. Ecol. Evol.
Volume:	5
Number:	5
Page Range:	S. 677 - 696
Date:	2021
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2397-334X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Ecology; Evolutionary Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57505