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When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load: The Smile-Frown Transition

Figure 4

Drug interaction profiles are dynamic.

(a) The degree of interaction, I(T) defined in Materials and Methods, is shown at different times from 12 h to 108 h: I(T) is negative for T≤24 h denoting synergy, but is positive for all T≥36 h denoting antagonism (vertical bars are s.e., 19 replicates). (b) A finer interaction measure than that used in (a), the degree of interaction obtained using the α-test defined in Materials and Methods produces a locus of drug interaction measures as a function of time. Consistent with (a), this measure changes sign, indicating a change of interaction near 30 h (note: −α is plotted). (c) The smile-frown transition resembles a phase transition when applying the α-test to i(θ,T) derived from MC4100 density data: the grey line shows the optimal drug combination that minimises i(θ,T), the red line shows the maximising combination. As the drug interaction profile ‘inverts’, the short-term optimal therapy shifts over a very short period to become the worst therapy beyond approximately 30 h. (The y-axis varies from θ = 0 (denoting an ERY-monotherapy) to θ = 1 (for a DOX-monotherapy), s.e. is shown as a pair of dashed lines.)

Figure 4