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
Gene duplication drives evolution by providing raw material for proteins with novel functions. An influential hypothesis by Ohno (1970) posits that gene duplication helps genes tolerate new mutations and thus facilitates the evolution of new phenotypes. Competing hypotheses argue that deleterious mutations will usually inactivate gene duplicates too rapidly for Ohno’s hypothesis to work. We experimentally tested Ohno’s hypothesis by evolving one or exactly two copies of a gene encoding a fluorescent protein in Escherichia coli through several rounds of mutation and selection. We analyzed the genotypic and phenotypic evolutionary dynamics of the evolving populations through high-throughput DNA sequencing, biochemical assays, and engineering of selected variants. In support of Ohno’s hypothesis, populations carrying two gene copies displayed higher mutational robustness than those carrying a single gene copy. Consequently, the double-copy populations experienced relaxed purifying selection, evolved higher phenotypic and genetic diversity, carried more mutations and accumulated combinations of key beneficial mutations earlier. However, their phenotypic evolution was not accelerated, possibly because one gene copy rapidly became inactivated by deleterious mutations. Our work provides an experimental platform to test models of evolution by gene duplication, and it supports alternatives to Ohno’s hypothesis that point to the importance of gene dosage.
