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- Title
Antibiotic collateral sensitivity is contingent on the repeatability of evolution.
- Authors
Nichol, Daniel; Rutter, Joseph; Bryant, Christopher; Hujer, Andrea M.; Lek, Sai; Adams, Mark D.; Jeavons, Peter; Anderson, Alexander R. A.; Bonomo, Robert A.; Scott, Jacob G.
- 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. The evolution of resistance to an antibiotic can render bacteria more susceptible, or more resistant, to a second antibiotic. Here, Nichol et al. provide evidence that the final outcome can be fairly stochastic and depends on the shape of the evolutionary fitness landscape.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-08098-6