  Bacteria evolve resistance to antibiotics by a multitude of mechanisms. A
central, yet unsolved question is how resistance evolution affects cell growth
at different drug levels. Here we develop a fitness model that predicts growth
rates of common resistance mutants from their effects on cell metabolism. We
map metabolic effects of resistance mutations in drug-free environments and
under drug challenge; the resulting fitness trade-off defines a Pareto surface
of resistance evolution. We predict evolutionary trajectories of
dosage-dependent growth rates and resistance levels, as well as the prevalent
resistance mechanism depending on drug and nutrient levels. These predictions
are confirmed by empirical growth curves and genomic data of E. coli
populations. Our results show that resistance evolution, by coupling major
metabolic pathways, is strongly intertwined with systems biology and ecology of
microbial populations.
