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Using a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages

Fig 3

The rate of adaptation has a complex relationship with antibiotic dose.

(A) Using IC50 dosages, growth rate adaptation (denoted α when defined in [14]) is greater for the 50/50 combination than for the EDEDEDED (“ERY—DOX”) and DEDEDEDE (“DOX—ERY”) sequential treatments. Adaptation can also be faster in the absence, rather than in the presence, of antibiotics. The right-hand plot shows each replicate separately (as a dot), indicating treatment clusters as coloured regions using the convex hulls of the datasets for each treatment type (whether no drug or single drug monotherapies, the 50/50 two-drug combination, or a sequential treatment). This shows sequential treatments minimise both final growth rate after eight seasons and the rate of adaptation. (B) Differences in the rate of adaptation in (A) are not accounted for by the duplication of the acrRAB operon, and sequential treatments do not prevent pump duplications. These coverage plots from sequenced populations at 24 h and 96 h show that both the combination (50/50) and sequential treatments (ERY/DOX) lead to the duplication of a genomic region from 273 Kb to 686 Kb that contains acrRAB. Left: the duplication was absent from all treatments after 24 h. Right: the duplication (the dark sector) is present in both the 50/50 combination and ERY—DOX sequential treatments after 96 h, but not in the no-drug control. Single nucleotide polymorphisms (SNPs) are highlighted as arrowheads next to the treatment in which they were observed. (S1 Data contains the data used in this figure.)

Fig 3