Abstract
Antibiotic resistance is a major concern in public health worldwide, thus there is much interest in characterizing the mutational pathways through which susceptible bacteria evolve resistance. Here we use experimental evolution to explore the mutational pathways toward aminoglycoside resistance, using gentamicin as a model, under low and high mutation supply rates. Our results show that both normo and hypermutable strains of Escherichia coli are able to develop resistance to drug dosages > 1,000-fold higher than the minimal inhibitory concentration for their ancestors. Interestingly, such level of resistance was often associated with changes in susceptibility to other antibiotics, most prominently with increased resistance to fosfomycin. Whole-genome sequencing revealed that all resistant derivatives presented diverse mutations in five common genetic elements: fhuA, fusA and the atpIBEFHAGDC, cyoABCDE, and potABCD operons. Despite the large number of mutations acquired, hypermutable strains did not pay, apparently, fitness cost. In contrast to recent studies, we found that the mutation supply rate mainly affected the speed (tempo) but not the pattern (mode) of evolution: both backgrounds acquired the mutations in the same order, although the hypermutator strain did it faster. This observation is compatible with the adaptive landscape for high-level gentamicin resistance being relatively smooth, with few local maxima; which might be a common feature among antibiotics for which resistance involves multiple loci.
Highlights
Darwinian evolution, through mutation, recombination, and horizontal transfer, enables bacteria to adapt to widely different environmental conditions (Lan and Reeves, 1996; Rosenberg, 2001; Didelot and Maiden, 2010)
Prior to the evolutionary process, a wild-type E. coli MG1655 strain and its dnaQ derivative were adapted to M9 minimal medium by serial passages into fresh media every 24 h during 7 days, equivalent to 56 generations, approximately
To minimize the confounding effects of mutations related to medium adaptation, both MG1655 and its dnaQ derivative were adapted to M9 minimal medium without antibiotic, during 56 generations prior to the evolutionary process
Summary
Through mutation, recombination, and horizontal transfer, enables bacteria to adapt to widely different environmental conditions (Lan and Reeves, 1996; Rosenberg, 2001; Didelot and Maiden, 2010). One important insight has been the realization that non-additive interactions among mutations can create adaptive landscapes that are rugged, that is, with divergent mutational pathways that lead to different local fitness peaks (de Visser and Krug, 2014) Adaptive dynamics under these circumstances can be complex, as illustrated by the apparent paradox that populations with a small mutation supply, limited in their adaptation speed, may have more chances of finding global fitness optima than populations with large ones (Rozen et al, 2008; Handel and Rozen, 2009). By substituting the best mutations less often, populations with smaller mutation supplies show more stochastic trajectories, which allows them to explore sub-optimal paths; incidentally reaching more distant, perhaps globally optimal, fitness peaks This phenomenon has been recently confirmed in an experimental model of beta-lactam resistance evolution (Salverda et al, 2017)
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