Fig. 1: Stochastic plasmid dynamics yield heterogeneous populations.

A Simulations of a plasmid dynamics model of a population growing in a drug-free medium from a single plasmid-bearing cell. The plasmid copy number (PCN) over time is depicted using a gradient of greens. The red area indicates the time interval during which the population was exposed to a lethal drug concentration. Most cells were killed during drug exposure (death events denoted with red circles), but a small fraction of cells carrying a high PCN survived and proliferated once the antibiotic was removed. B Density distribution of end-point PCNs (maximum) estimated using the computational model. The black line represents the PCN distribution obtained using the parameter values described in Table S2, while the green lines depict other simulations resulting in distributions with larger variances. C Probability density functions of Normal distributions with a fixed mean and increasing standard deviations. The dotted line corresponds to the case when the PCN distribution has zero variance. As the variance of the PCN distribution increases, the fraction of cells with an increased probability of survival at high drug concentrations also increases. D PCN distributions obtained for different antibiotic concentrations: the black line represents the drug-free environment, and the distributions obtained after exposing the heterogeneous population to increasing drug concentrations are depicted in a gradient of red. E Mean PCN (solid line) of the PCN distributions obtained after exposing the population to a range of antibiotic concentrations. The red area corresponds to the frequency of PCN in the population for each drug concentration. The dotted line illustrates the minimum inhibitory concentration (MIC) of the homogeneous population. Note that selection for cells with multiple plasmids occurs even at sub-MIC concentrations. F Mean PCN at the end of each season in experiments performed with increasing concentrations of antibiotics (low doses in yellow and a lethal dose in red). Note how the increase in mean PCN observed during the selective phase of the experiment is proportional to the drug concentration. The antibiotic was removed in season 3, and the mean PCN exhibited by the population is restored to levels displayed before drug exposure.