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Collateral sensitivity is contingent on the repeatability of evolution

View ORCID ProfileDaniel Nichol, Joseph Rutter, Christopher Bryant, Peter Jeavons, View ORCID ProfileAlexander RA Anderson, Robert A Bonomo, Jacob G Scott
doi: https://doi.org/10.1101/185892
Daniel Nichol
1Department of Computer Science, University of Oxford, Oxford, UK
2Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
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Joseph Rutter
3Research Service, Louis Stokes Department of Veterans Affairs Hospital, Cleveland, OH, USA
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Christopher Bryant
4Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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Peter Jeavons
1Department of Computer Science, University of Oxford, Oxford, UK
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Alexander RA Anderson
5Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Robert A Bonomo
3Research Service, Louis Stokes Department of Veterans Affairs Hospital, Cleveland, OH, USA
4Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
6Departments of Biochemistry, Microbiology, Molecular Biology and Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
7Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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Jacob G Scott
7Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
8Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK
9Departments of Translational Hematology and Oncology Research and Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA
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Abstract

Antibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of sequences of drugs exhibiting collateral sensitivity, wherein the evolution of resistance to a first drug renders a population more susceptible to a second. Here, we demonstrate that sequential multi–drug therapies derived from in vitro evolution experiments can have overstated therapeutic benefit – potentially suggesting a collaterally sensitive response where cross resistance ultimately occurs. The evolution of drug resistance need not be genetically or phenotypically convergent, and where resistance arises through divergent mechanisms, the efficacy of a second drug can vary substantially. We first quantify the likelihood of this occurring by use of a mathematical model parametrised by a set of small combinatorially complete fitness landscapes for Escherichia coli. We then verify, through in vitro experimental evolution, that a second–line drug can indeed stochastically exhibit either increased susceptibility or increased resistance when following a first. Genetic divergence is confirmed as the driver of this differential response through targeted sequencing. These results indicate that the present methodology of designing drug regimens through experimental collateral sensitivity analysis may be flawed under certain ecological conditions. Further, these results suggest the need for a more rigorous probabilistic understanding of the contingencies that can arise during the evolution of drug resistance.

Footnotes

  • ↵* daniel.nichol{at}icr.ac.uk (DN); scottj10{at}ccf.org (JGS)

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted September 07, 2017.
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Collateral sensitivity is contingent on the repeatability of evolution
Daniel Nichol, Joseph Rutter, Christopher Bryant, Peter Jeavons, Alexander RA Anderson, Robert A Bonomo, Jacob G Scott
bioRxiv 185892; doi: https://doi.org/10.1101/185892
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Collateral sensitivity is contingent on the repeatability of evolution
Daniel Nichol, Joseph Rutter, Christopher Bryant, Peter Jeavons, Alexander RA Anderson, Robert A Bonomo, Jacob G Scott
bioRxiv 185892; doi: https://doi.org/10.1101/185892

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