29 October 2020

Strategies in evolutionary medicine aim to thwart the evolution of drug resistance by using combinations of drugs that demonstrate “collateral sensitivity,” which is when mutants that resist Drug ‘A’ increase susceptibility to Drug ‘B’. Problematically, it often turns out that resistance and susceptibility are not inextricably linked, and some rare mutations exist that resist both drugs. Most technologies cannot quantify the prevalence of collateral sensitivity. We utilize a laboratory evolution platform that is perfect for doing so. Rather than identifying the most resistant mutants in Drug ‘A’, we can collect virtually all possible mutations that resist Drug ‘A’ and quantify their resistance to Drug ‘B’. Characterizing collateral sensitivity at this scale can reveal general mechanisms that turn advantageous mutations into costly ones. It can also inform about the degree of modularity in biological systems, ie, the degree to which mutations have limited v. multifaceted effects.