Collateral sensitivity is contingent on the repeatability of evolution
Daniel Nichol, Joseph Rutter, Christopher Bryant, Andrea M Hujer, Peter Jeavons, Alexander RA Anderson, Robert A Bonomo, Jacob G Scott
Received: 23rd October 17
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 fro in vitro evolution experiments can, in some cases, 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.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.