Using a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages
Fig 5
A mathematical model indicates frequency-dependent selection for the pump duplication can cause a nonreciprocal collateral sensitivity profile with respect to population densities.
(A) The first two columns indicate modelled internal drug concentrations in three cell phenotypes (dark blue: “wild-type” cells not expressing the pump; red: the pump gene is expressed; dark grey: two pump genes are expressed). The third column shows modelled population densities through time, indicating the frequencies of each phenotype within that density. The different drugs select for resistant (pump-expressing) and susceptible (pump-not-expressed) phenotypes at different rates, despite both having been calibrated to equal inhibitory effect (namely IC50) on a population consisting almost exclusively of wild-type cells by the end of day 1. These simulations show that monotherapies consisting of either drug select for different population structures, each having different frequencies of the pump gene and its duplication, depending on which drug is being applied. Thus, given n days of adaptation to DOX followed by adaptation to ERY, after the switch, density decreases. (B) Implementing the (n+1) protocol in the model is consistent with the data of Fig. 4. (S1 Data contains the data used in this figure.)