The population genetics of collateral resistance and sensitivity

  1. Sarah M Ardell
  2. Sergey Kryazhimskiy  Is a corresponding author
  1. University of California, San Diego, United States


Resistance mutations against one drug can elicit collateral sensitivity against other drugs. Multi-drug treatments exploiting such trade-offs can help slow down the evolution of resistance. However, if mutations with diverse collateral effects are available, a treated population may evolve either collateral sensitivity or collateral resistance. How to design treatments robust to such uncertainty is unclear. We show that many resistance mutations in Escherichia coli against various antibiotics indeed have diverse collateral effects. We propose to characterize such diversity with a joint distribution of fitness effects (JDFE) and develop a theory for describing and predicting collateral evolution based on simple statistics of the JDFE. We show how to robustly rank drug pairs to minimize the risk of collateral resistance and how to estimate JDFEs. In addition to practical applications, these results have implications for our understanding of evolution in variable environments.

Data availability

All code is available on GitHub. All data are available as Source Data files, included with the manuscript.

Article and author information

Author details

  1. Sarah M Ardell

    Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sergey Kryazhimskiy

    Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9128-8705


Burroughs Wellcome Fund (1010719.01)

  • Sergey Kryazhimskiy

Alfred P. Sloan Foundation (FG-2017-9227)

  • Sergey Kryazhimskiy

Hellman Foundation

  • Sergey Kryazhimskiy

National Institutes of Health (1R01GM137112)

  • Sergey Kryazhimskiy

National Institutes of Health (1T32GM133351-01)

  • Sarah M Ardell

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

Reviewing Editor

  1. Richard A Neher, University of Basel, Switzerland

Publication history

  1. Received: August 22, 2021
  2. Accepted: December 6, 2021
  3. Accepted Manuscript published: December 10, 2021 (version 1)
  4. Version of Record published: January 18, 2022 (version 2)


© 2021, Ardell & Kryazhimskiy

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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  1. Sarah M Ardell
  2. Sergey Kryazhimskiy
The population genetics of collateral resistance and sensitivity
eLife 10:e73250.

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