Antibiotic collateral sensitivity is contingent on the repeatability of evolution.
Nat Commun 2019 Jan 18; 10(1):334
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.
Nichol, Daniel; Rutter, Joseph; Bryant, Christopher; Hujer, Andrea M; Lek, Sai; Adams, Mark D; Jeavons, Peter; Anderson, Alexander R A; Bonomo, Robert A; and Scott, Jacob G, "Antibiotic collateral sensitivity is contingent on the repeatability of evolution." (2019). Faculty Research 2019. 26.