High potency of sequential therapy with only beta-lactam antibiotics
- Kiel University, Germany
- University of Kiel, Germany
- Borstel Research Centre, Germany
Abstract
Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution-informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous, as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only β-lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross-resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs.
Data availability
Sequencing data have been deposited at NCBI under the BioProject number: PRJNA704789. All other data is provided in the supplementary source data files.
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Cellular hysteresis as a principle to maximize the efficacy of antibiotic therapy - Results on extinction frequencieshttps://doi.org/10.1073/pnas.1810004115.
Article and author information
Author details
Hinrich Schulenburg
Funding
Deutsche Forschungsgemeinschaft (SCHU 1415/12)
- Hinrich Schulenburg
Deutsche Forschungsgemeinschaft (EXC 2167-390884018)
- Stefan Niemann
- Hinrich Schulenburg
Deutsche Forschungsgemeinschaft (GRK 2501)
- Stefan Niemann
- Hinrich Schulenburg
Max-Planck-Gesellschaft (IMPRS Stipend)
- Aditi Batra
Max-Planck-Gesellschaft (Fellowship)
- Hinrich Schulenburg
Leibniz-Gemeinschaft (EvoLUNG)
- Stefan Niemann
- Hinrich Schulenburg
Deutsche Forschungsgemeinschaft (project 407495230)
- Sören Franzenburg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Batra et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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High potency of sequential therapy with only beta-lactam antibiotics
eLife 10:e68876.
https://doi.org/10.7554/eLife.68876
Further reading
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- Evolutionary Biology
- Epidemiology and Global Health
- Microbiology and Infectious Disease
- Genetics and Genomics
eLife is pleased to present a Special Issue to highlight recent advances in the growing and increasingly interdisciplinary field of evolutionary medicine.
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- Evolutionary Biology
Signs of ageing become apparent only late in life, after organismal development is finalized. Ageing, most notably, decreases an individual’s fitness. As such, it is most commonly perceived as a non-adaptive force of evolution and considered a by-product of natural selection. Building upon the evolutionarily conserved age-related Smurf phenotype, we propose a simple mathematical life-history trait model in which an organism is characterized by two core abilities: reproduction and homeostasis. Through the simulation of this model, we observe (1) the convergence of fertility’s end with the onset of senescence, (2) the relative success of ageing populations, as compared to non-ageing populations, and (3) the enhanced evolvability (i.e. the generation of genetic variability) of ageing populations. In addition, we formally demonstrate the mathematical convergence observed in (1). We thus theorize that mechanisms that link the timing of fertility and ageing have been selected and fixed over evolutionary history, which, in turn, explains why ageing populations are more evolvable and therefore more successful. Broadly speaking, our work suggests that ageing is an adaptive force of evolution.
