Figure 2: A simple model suggests nearly all antibiotic-stress interactions exhibit regions of antibiotic-potentiated selection for or against resistance.

Antibiotics applied in combination produce interactions which are coarsely visualized by the minimum inhibitory concentration (MIC) line, which separates growth and no growth regions in drug–drug concentration space. Interactions can range from drug X suppressing, to buffering, to augmenting the effects of drug Y (a–c, respectively). MIC lines of an X-resistant strain (X^R, red) are approximated by geometrically scaling the MIC lines of the X-sensitive strain (X^S, green) along the drug x axis, reflecting the diminished effective levels of that drug to the resistant strain (grey arrow in a). While resistance to drug X does not change the MIC to drug Y alone (the green and red lines coincide along Y-axis, [X]=0), adding sub-inhibitory levels of drug X tends to separate the MIC lines of the X^R and X^S strains, exposing regions of ‘threshold selection’ where one strain grows but the other is fully inhibited (a, only X^S strain can grow in the pale green region with no red stripes; c, only X^R strain can grow in the red striped region with no green background). This potentiated threshold selection occurs along gradients of drug Y at a fixed positive concentration of X (wedge at [X]=x′) for every drug interaction except for buffering (b), where the MIC lines coincide. Qualitatively, these regions of selection between sensitive and resistant MIC lines are observed in differential inhibition assays over diffusing Y gradients (Compare wedges in plots and in schematic differential inhibition assays directly above). The model can be refined to include other positive growth isoclines which, treated similarly to the MIC, generate less intense selection windows ^48,49 with the same dependence on the shape of the stress interaction.