Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance
The probability distributions for accessibility of the peaks of the Amp landscape for different steering regimes. The initial distribution is μ = [1/2N,…,1/2N]. When Amp is given first any of the three peaks of the landscape are accessible, with the most resistant genotype 1111 being most likely. If Sam is given first to steer the population to its sole peak 1111, then resistance to Amp will be guaranteed when it is applied. Alternatively, if Sam is given followed by Cpr, then the population evolves to the local optimum genotype 0110 of the Cpr landscape. If Amp is applied to this primed population the global optimum, 1111, is inaccessible.