1. Evolutionary Biology
Download icon

Multi-step vs. single-step resistance evolution under different drugs, pharmacokinetics and treatment regimens

  1. Claudia Igler  Is a corresponding author
  2. Jens Rolff
  3. Roland Regoes  Is a corresponding author
  1. ETH Zurich, Switzerland
  2. Freie Universität Berlin, Germany
Research Article
  • Cited 2
  • Views 2,078
  • Annotations
Cite this article as: eLife 2021;10:e64116 doi: 10.7554/eLife.64116


The success of antimicrobial treatment is threatened by the evolution of drug resistance. Population genetic models are an important tool in mitigating that threat. However, most such models consider resistance emergence via a single mutational step. Here, we assembled experimental evidence that drug resistance evolution follows two patterns: i) a single mutation, which provides a large resistance benefit, or ii) multiple mutations, each conferring a small benefit, which combine to yield high-level resistance. Using stochastic modeling we then investigated the consequences of these two patterns for treatment failure and population diversity under various treatments. We find that resistance evolution is substantially limited if more than two mutations are required and that the extent of this limitation depends on the combination of drug type and pharmacokinetic profile. Further, if multiple mutations are necessary, adaptive treatment, which only suppresses the bacterial population, delays treatment failure due to resistance for a longer time than aggressive treatment, which aims at eradication.

Data availability

All data and code generated or analysed during this study are included in the manuscript and supporting files. Source code has been provided for Figures 2-4, as well as S2-S17 in the form of an R package. Source data has been provided for Table 1, Figure 1B and S1.

The following previously published data sets were used
    1. Melnyk A
    2. Wong A
    3. Kassen R
    (2015) The fitness costs of antibiotic resistance mutations
    Dryad Digital Repository: http://doi.org/10.5061/dryad.5rc47.

Article and author information

Author details

  1. Claudia Igler

    Theoretical Biology, ETH Zurich, Zurich, Switzerland
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7777-546X
  2. Jens Rolff

    Institute for Biology, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1529-5409
  3. Roland Regoes

    Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8319-5293


Volkswagen Foundation (96517)

  • Claudia Igler
  • Jens Rolff
  • Roland Regoes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ben S Cooper, Mahidol University, Thailand

Publication history

  1. Received: October 18, 2020
  2. Accepted: May 4, 2021
  3. Accepted Manuscript published: May 18, 2021 (version 1)
  4. Version of Record published: June 7, 2021 (version 2)


© 2021, Igler 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.


  • 2,078
    Page views
  • 215
  • 2

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Evolutionary Biology
    Chenlu Di et al.
    Research Article Updated

    Advances in genome sequencing have improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Recent genomic adaptation at disease genes has not been well characterized. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between mendelian, non-infectious disease genes and non-disease genes across distinct human populations from the 1000 Genomes Project. We find that mendelian disease genes have experienced far less selective sweeps compared to non-disease genes especially in Africa. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is almost non-existent at disease genes with higher recombination rates or lower numbers of associated disease variants. Because segregating recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. These results suggest that disease genes suffer from a transient inability to adapt as fast as the rest of the genome.

    1. Evolutionary Biology
    2. Microbiology and Infectious Disease
    Jennifer E Jones et al.
    Research Article Updated

    The influenza A virus (IAV) genome consists of eight negative-sense viral RNA (vRNA) segments that are selectively assembled into progeny virus particles through RNA-RNA interactions. To explore putative intersegmental RNA-RNA relationships, we quantified similarity between phylogenetic trees comprising each vRNA segment from seasonal human IAV. Intersegmental tree similarity differed between subtype and lineage. While intersegmental relationships were largely conserved over time in H3N2 viruses, they diverged in H1N1 strains isolated before and after the 2009 pandemic. Surprisingly, intersegmental relationships were not driven solely by protein sequence, suggesting that IAV evolution could also be driven by RNA-RNA interactions. Finally, we used confocal microscopy to determine that colocalization of highly coevolved vRNA segments is enriched over other assembly intermediates at the nuclear periphery during productive viral infection. This study illustrates how putative RNA interactions underlying selective assembly of IAV can be interrogated with phylogenetics.