Multi-scale predictions of drug resistance epidemiology suggest a new design principle for rational drug design.

Theoretical treatments of evolutionary dynamics tend to model the probability that a single "resistant" species will arise in a population. However, experimental studies have identified a diversity of mutations that can lead to genetic resistance. By quantitatively predicting mutations that occur across an entire drug target during treatment, we identify and bridge a fundamental gap in drug resistance theory: that nucleotide/codon substitution biases can dictate which resistant variants arise in the clinic. We find that the likeliest mutation can beat the most resistant mutation. This creates a new paradigm in drug resistance that we term "survival of the likeliest". We use epidemiological evidence in leukemia, isogenic experiments, stochastic dynamics, and large-scale simulations to support this theory. In addition, this work has strong implications for drug design because not all resistance liabilities are created equal. In pathogenic populations that exhibit survival of the likeliest, exploiting the least likely evolutionary path can minimize resistance across a population during widespread drug use, even when a vulnerability-free molecule or combination cannot be made. Data and Code Availabilityhttps://github.com/pritchardlabatpsu/SurvivalOfTheLikeliest/