Antibiotic collateral sensitivity is contingent on the repeatability of evolution.
Document Type
Article
Publication Date
1-18-2019
Keywords
JMG
JAX Source
Nat Commun 2019 Jan 18; 10(1):334
Volume
10
Issue
1
First Page
334
Last Page
334
ISSN
2041-1723
PMID
30659188
DOI
https://doi.org/10.1038/s41467-018-08098-6
Abstract
Antibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of collateral sensitivities, wherein evolution under a first drug induces susceptibility to a second. Here, we report that sequential drug regimens derived from in vitro evolution experiments may have overstated therapeutic benefit, predicting a collaterally sensitive response where cross-resistance ultimately occurs. We quantify the likelihood of this phenomenon by use of a mathematical model parametrised with combinatorially complete fitness landscapes for Escherichia coli. Through experimental evolution we then verify that a second 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 and whole genome sequencing. Taken together, these results highlight that the success of evolutionarily-informed therapies is predicated on a rigorous probabilistic understanding of the contingencies that arise during the evolution of drug resistance.
Recommended Citation
Nichol D,
Rutter J,
Bryant C,
Hujer A,
Lek S,
Adams M,
Jeavons P,
Anderson A,
Bonomo R,
Scott J.
Antibiotic collateral sensitivity is contingent on the repeatability of evolution. Nat Commun 2019 Jan 18; 10(1):334