Resistance variability affects the dynamics of evolutionary adaptation to drugs.

<p>(A) Simulation results from a theoretical model of resistance evolution in a morbidostat [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002299#pbio.1002299.ref011" target="_blank">11</a>]: IC₅₀ increase over time for a drug with narrow DEC and two available large-effect mutations (magenta) or none (gray); light lines are sample runs; dark lines are mean of 200 runs; inset: distribution of relative IC₅₀ changes used in simulations (Materials and Methods). (B) Same as in panel A for wider DEC (Materials and Methods). (C, D) Results from morbidostat laboratory evolution experiments: IC₅₀ increase over time for nitrofurantoin (C) and chloramphenicol (D); light lines are individual runs; dark lines are mean, error bars standard deviation; shaded region in C indicates early phase during which large-effect mutations fix (Materials and Methods). (E) Mutated loci in nitrofurantoin (left) and chloramphenicol (right)-resistant clones after 10 and 21 d, respectively. Filled pie segments show evolution replicates in which genes were mutated; (P) indicates promoter mutations. Bar chart shows diversity (entropy) of mutations under nitrofurantoin (magenta) and chloramphenicol (gray); <i>p</i> < 0.002 (**) and <i>p</i> < 0.0003 (***) from two-sample <i>t</i> test; error bars show jackknife standard error (Materials and Methods). Numerical data is in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002299#pbio.1002299.s001" target="_blank">S1 Data</a>. Whole genome sequencing results are in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002299#pbio.1002299.s009" target="_blank">S2 Table</a> and <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002299#pbio.1002299.s010" target="_blank">S3 Table</a>.