Evolutionary pathways to collateral sensitivity

Drug resistance represents a vast problem that has yet to successfully addressed. Recent work focuses on collateral sensitivities, where evolution of resistance under drug A results in susceptibility to drug B. At present, studies in both cancer cells and bacteria populations have demonstrated that collateral sensitivity is unpredictable and nonrepeatable. This can be attributed to the wide array of mutations that can occur under the stress of the drug A and the low replicate size used in the experiments. Here, we propose using a barcoded yeast system to track a large population of yeast as they develop resistance to drug A then are subsequently challenged by drug B. This system tracks hundreds of thousands of replicate yeast lineages, thus revealing the full spectrum of adaptive mutants that protect against drug A. Experiments using this system will provide a more quantitative understanding of the likelihood of collateral sensitivity, as well as the evolutionary paths that lead to collateral sensitivities.