Resolution:
## Figure 4.
Phase Diagram for Salicylate-Chloramphenicol Interactions.a. The concentration of salicylate, S* (in mM), at which growth is maximal depends
on the external concentration of antibiotic. A transition occurs between the low antibiotic
regime, where the presence of salicylate is harmful, to the high antibiotic where
the presence of salicylate increases the growth of cells. Red, tetracylcline; Blue,
chloramphenicol. Concentrations for both drugs measured in μg/mL. Curves, numerical
calculation from model; circles, estimates of S* from experiments at single concentrations
of A. Maxima were estimated using cubic spline interpolation between data points at
different concentrations of salcilyate. Error bars, concentrations corresponding to
+/− 1% of maximum. b. Apparent MIC, defined as the minimum concentration of antibiotic (red, tetracycline;
blue, chloramphenicol; both in units of μg/mL) at which growth is reduced to δ = 0.5.
While the quantitative results depend on the precise definition of MIC, the qualitative
features do not depend on the choice of δ. c. Cost-benefit theory predicts general properties of drug interactions as a function
of the maximum inducible benefit β_{max} and the concentration of inducer, S. Solid line, phase boundary between synergistic
and antagonistic drug interactions. Dashed line, phase boundary between antagonistic
and suppressive interactions. In general, a higher value of the β_{max} increases the antagonism between drug pairs at a given concentration of drug S. Parameters
characterizing individual drugs include K_{S} and K_{ind}, which characterize, respectively, the cost of drug S and the corresponding induction
of resistance systems (e.g. efflux pumps), and K_{A} and n, which characterize the cost of drug A. By contrast, β_{max} couples the individual effects of two drugs. Insets, heat maps of two-dimensional
growth surfaces for 3 cell strains in the presence of Salicylate (Sal) and Chloramphenicol
(Cm); top: β_{max} = 1.15 (WT cells; suppressive), β_{max} = 0.19 (mar mutant, antagonistic), and β_{max} = −0.15 (tolC mutant, synergistic). See also Additional file 1: Figure S3.
Wood and Cluzel |